CN1067892A - The preparation method of new pyrrolo-[2,3-b] pyridine derivate - Google Patents

The preparation method of new pyrrolo-[2,3-b] pyridine derivate Download PDF

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CN1067892A
CN1067892A CN92102170A CN92102170A CN1067892A CN 1067892 A CN1067892 A CN 1067892A CN 92102170 A CN92102170 A CN 92102170A CN 92102170 A CN92102170 A CN 92102170A CN 1067892 A CN1067892 A CN 1067892A
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compound
pyridine
definition
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alkyl
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C·布赖芬
M·埃利布林
S·卡尔松
R·卡特
T·屈勒
P·努德贝里
I·施塔克
A·施文松
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AstraZeneca AB
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Astra AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Abstract

The invention discloses the new therapeutical active compound of following formula.

Description

The preparation method of new pyrrolo-[2,3-b] pyridine derivate
The object of the invention provides acceptable salt on new compound and the therapeutics thereof, and they can suppress the gastric acid secretion of external cause or internal cause stimulation, thereby can be used for prevention and treatment stomach ulcer.
The invention still further relates to the purposes of The compounds of this invention, be used to suppress the Mammals gastric acid secretion of (comprising the people).More particularly, The compounds of this invention can be used to prevent and treat the mammiferous gastroenteritis disease that comprises the people and with the hydrochloric acid in gastric juice diseases associated, as gastritis, stomach ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Ellison syndromes.In addition, The compounds of this invention also can be used for other gastrointestinal dysfunction disease that need suppress the stomachial secretion effect, for example gastrinoma patient, and acute upper stomach intestinal bleeding patient.The patient who nurses with postoperative reinforcement before they also can be used for performing the operation sucks and tonus ulcer to prevent acid.The invention still further relates to and contain at least a The compounds of this invention or its therapeutics acceptable salt as the medicinal compositions of activeconstituents.In addition, the present invention relates to the preparation method of these new compounds, and active compound of the present invention is used to prepare the purposes of the medicinal compositions with above-mentioned medical functions.
Following document discloses some pyrrolo-[2,3-b] pyridine compounds:
Saify Pak.J.Pharmacol.86 Vol 2（2）pp 43-36（1985），Saify，J.Pharm.Univ.Kar.2（2）：99-103（1984），
Timpe et al.J.Prakt.Chem.80 Vol 322（3）pp 517-21（1980）Ogali et al.，Indian Journal of Chemistry Vol.27B，656-651（1988）.
We have found that following formula I compound is effective gastric acid secretion inhibitor.Formula I compound is by suppressing gi tract H +K +-ATPase enzyme and bring into play the inhibitor effect.
The compounds of this invention is following formula I compound or its pharmacy acceptable salt,
Figure 921021704_IMG29
In the formula
The X representative
Figure 921021704_IMG30
R 1Represent H, low alkyl group ,-CH 2-O-R 7, halogen, phenyl or quilt (1-6C) alkyl, (1-6C) alkoxyl group, (1-6C) acyl group, halogen, CF 3, CN, NH 2, NO 2Or (1-6C) phenyl that replaces of alkoxy carbonyl;
R 2Represent H, low alkyl group, CH 2CN,
Figure 921021704_IMG31
, halogen, O-R 8,
Figure 921021704_IMG32
, S-CN, CH 2OH, CH 2C ≡ CH, CF 3, CH 2NC, NH 2;
R 3Represent H, low alkyl group, CF 3, O-R 9, NH 2, low-grade alkyl amino, two elementary alkyl amido, halogen, CN,
Figure 921021704_IMG33
, S-R 10Or NHCOR 10;
R 4And R 5Can be identical or different, represent H, low alkyl group, CN, halogen, O-R 11, NO 2, NH 2, low-grade alkyl amino, two elementary alkyl amido, S-R 12, NHCOR 13, NHCOOR 14, CF 3Or CO-R 15;
R 6, R 7, R 8, R 9, R 11And R 13Can be identical or different, represent H or low alkyl group;
R 10Represent low alkyl group or phenyl lower alkyl;
R 12And R 14Can be identical or different, represent low alkyl group;
R 15Represent H, low alkyl group, OH or lower alkoxy; Condition is R 1And R 2Not H simultaneously.
In this article; when " rudimentary " speech was used for alkyl, alkoxyl group, alkylamino, dialkyl amido, alkylthio, alkyl sulfinyl, octadecyloxy phenyl sulfenyl, phenylalkyl sulfinyl, amido or carbalkoxy, it comprised straight chain and the branched hydrocarbyl that contains 6 carbon atoms at the most.
" halogen " speech comprises fluorine, chlorine, bromine and iodine.
The inequality mixture of two kinds of pure enantiomorphs, racemic mixture and two kinds of enantiomorphs includes within the scope of the present invention.Should be understood that all possible diastereomeric form formula (pure enantiomorph or racemic mixture) includes within the scope of the present invention.The derivative of formula I compound with biological function of formula I compound is also included within the scope of the invention.
Depend on processing condition and raw material, the finished product of formula I obtain with the form of neutrality or salt.The free alkali of these the finished product or free acid with and salt both include within the scope of the present invention.
The acid salt of new compound can be converted into free alkali according to currently known methods with alkaline reagents (as alkali) or by ion-exchange.The free alkali that obtains also can form salt with organic acid or mineral acid.In the preparation of acid salt, preferably use those can form the acid of acceptable suitable salt on the therapeutics.
These sour examples are haloid acid, sulfonic acid, phosphoric acid, nitric acid, aliphatic series, alicyclic ring, fragrance or heterocyclic carboxylic acid or sulfonic acid, for example formic acid, acetate, propionic acid, Succinic Acid, oxyacetic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, toxilic acid, hydroxymaleic acid, pyruvic acid, P-hydroxybenzoic acid, embellic acid, methylsulfonic acid, ethyl sulfonic acid, ethylenehydrinsulfonic acid, vinyl sulfonic acid, halogeno-benzene sulfonic acid, toluenesulphonic acids or naphthene sulfonic acid.
These or other the salt (as picrate) of new pyrrolo-[2,3-b] pyridine can be used as the purifying agent of the free alkali of acquisition.The salt of alkali can generate, separate from solution, regains more highly purified free alkali then from the new soln of this salt.
The base addition salt of new compound of the present invention can be converted into its sour form with mineral acid or organic acid, and then be converted into salt suitable on the therapeutics, for example, obtain sodium salt and sylvite respectively by adduction NaOH and KOH.
Preferred formula I compound is:
1. wherein X is
Figure 921021704_IMG34
Or-CH 2-and R 6Described as defined above compound.
2. R wherein 1Be low alkyl group, can substituted phenyl, CH 2OR 7Or halogen and R 7The aforesaid compound of definition.
3. R wherein 2Be H, low alkyl group, CH 2C ≡ CH, CH 2OH, CH 2CN,
Figure 921021704_IMG35
, CH 2NC, NH 2,
Figure 921021704_IMG36
, SCN, halogen or CF 3Compound.
4. R wherein 3Be H, low alkyl group, O-R 9, NH 2, low-grade alkyl amino, two elementary alkyl amido, C ≡ N, S-R 10,
Figure 921021704_IMG37
, halogen, CF 3Or NHCOR 10, R 9And R 10Described as defined above compound.
5. R wherein 4And R 5Can be identical or different, they are selected from H, low alkyl group, C ≡ N, halogen O-R 10, NO 2, NH 2, low-grade alkyl amino, two elementary alkyl amido, S-R 12, NHCOR 13, CF 3Or,
Figure 921021704_IMG38
, R 11, R 12, R 13And R 15Described as defined above compound.
Preferred formula I compound is:
1. wherein X is
Figure 921021704_IMG39
Or-CH 2-compound.
2. R wherein 1Be CH 3, C 2H 5, CH(CH 3) 2, CH 2CH 2CH 3, Cl, Br or phenyl compound.
3. R wherein 2Be H, CH 3, C 2H 5, CH 2CN,
Figure 921021704_IMG40
, F, Cl, Br, SCN, CH 2OH, CH 2C ≡ CH, CF 3Or CH 2The compound of NC.
4. R wherein 3Be H, CH 3, C 2H 5, CH(CH 3) 2,
CH 2CH 2CH 3, CF 3, OH, OCH 3, OC 2H 5, OCH(CH 3) 2, NH 2, NHCH 3, NHC 2H 5, N(CH 3) 2, N(C 2H 5) 2, F, Cl, Br, S-CH 3, S-C 2H 5, S-CH 2CH 2
Figure 921021704_IMG41
, NHCOCH 3Compound.
5. R wherein 4And R 5Can be identical or different, they are selected from
H，CH 3，C 2H 5，CH（CH 3） 2，F，Cl，Br，OH，OCH 3，OC 2H 5，OCH（CH 3） 2，NO 2，NH 2，NHCH 3，NHC 2H 5，N（CH 3） 2，N（C 2H 5） 2，S-CH 3，CF 3.
Compound.
Radicals R 34,5 or 6 of formula I compound, preferably at 5 or 6.
Radicals R 4And R 52,3,4,5 or 6 of phenyl ring.
Most preferred The compounds of this invention is:
Figure 921021704_IMG42
Other preferred compound of the present invention is:
Figure 921021704_IMG44
Figure 921021704_IMG45
Preparation
The present invention also provides the preparation method of generalformula.These compounds can prepare with following method:
A. general formula II compound:
R wherein 1, R 2And R 3Described as defined above;
General formula III compound:
Wherein X, R 4, R 5Described as defined above, Y leavings group such as halogen, tosyloxy or mesyloxy;
With above-mentioned general formula II compound and the reaction of general formula III compound, obtain wherein X, R 1, R 2, R 3, R 4And R 5Described as defined above formula I compound, this reaction is suitable for carrying out in solvent.React employed solvent preferably polar solvent such as acetonitrile or dimethyl formamide or alcohol (for example ethanol or Virahol).
The scope of temperature of reaction is about 20 ℃ of boiling temperatures to solvent usually, preferably about 20 ℃-80 ℃.The scope in reaction times is about 0.1-96 hour.
B. X is C=0 by reducing wherein, R 1, R 2, R 3, R 4And R 5Described as defined above formula I compound, for example with itself and reductive agent such as NaBH 4, LiAlH 4Reaction or catalytic hydrogenation make wherein that X is CHOH, R 1, R 2, R 3, R 4And R 5Described as defined above formula I compound.
C. incite somebody to action wherein X, R 1, R 3, R 4And R 5Described as defined above, R 2Be 0(1-6C) formula I compound and the dealkylation agent such as the B(Br of alkyl) 3Or (CH 3) 3The SiI reaction makes wherein R 2Be OH, X, R 1, R 3, R 4And R 5Described as defined above formula I compound.
D. wherein X is CHOH, R 1, R 2, R 3, R 4And R 5Described as defined above formula I compound and formula IV compound reaction, making wherein, X is CHO-R 6, R 1, R 2, R 3, R 4And R 5Described as defined above formula I compound.Formula IV compound is:
R 6-Z Ⅳ
R wherein 6Described as defined above, Z is the esterified hydroxy groups of reactive behavior.
E. incite somebody to action wherein X, R 1, R 2, R 3And R 5Described as defined above, condition is R 5With R 4Difference, R 4Be 2-O(C 1-C 6Alkyl) formula I compound and dealkylation agent such as B(Br) 3Or (CH 3) 3The SiI reaction makes wherein R 4Be 2-OH, R 5With R 4Inequality, X, R 1, R 2And R 3Described as defined above formula I compound.
Embodiment 1
2-methyl-7-(2-phenylethyl)-preparation of pyrrolo-[2,3-b] pyridine
With 85mg(0.64mmol) 2-methyl-pyrrolo-[2,3-b] pyridine, 140mg(0.76mmol) the 1ml acetonitrile solution of (2-bromotrifluoromethane) benzene refluxed 40 hours.With solvent evaporation, residuum is handled with ether.The solid that forms separates after filtration, obtains 188mg(62%) 2-methyl-7-(2-phenylethyl) pyrrolo-[2,3-b] pyridine hydrobromide salt
（ 1H-NMR，500 MHz，CDCl 3）2.78（s，3H），3.44（t，2H），5.40（t，2H）6.44（s，1H），6.97（dd，2H），7.08（dd，1H），7.18（m，3H），7.31（d，1H），8.17（d，1H）.
Embodiment 2
3-chloro-2-methyl-7-(2-phenylethyl) pyrrolo-[2,3-b] pyridine hydrobromide salt
With 28.4mg(0.17mmol) 3-chloro-2-methylpyrrole also [2,3-b] pyridine, 36mg(0.2mmol) the 0.4ml dimethyl formamide solution of (2-bromotrifluoromethane) benzene is 80 ℃ of heating 20 hours down.With solvent evaporation.The solid that forms is handled with ethyl ester, and filtering separation obtains 30mg(50%) 3-chloro-2-methyl-7-(2-phenylethyl) pyrrolo-[2,3-b] pyridine hydrobromide salt.
（ 1H-NMR，500 MHz，CDCl 3）2.77（s，3H），3.45（t，2H），5.40（t，2H），6.95（dd，2H），7.14（dd，1H），7.2（m，3H），7.28（d，1H），8.24（d，1H）.
Embodiment 3
3-cyanogen methyl-2-methyl-7-(2-phenylethyl) pyrrolo-[2,3-b] pyridine
With 130mg(0.76mmol) 3-cyanogen methyl-2-methylpyrrole also [2,3-b] pyridine, 150mg(0.81mmol) acetonitrile solution of 2 bromoethyl benzene refluxed 40 hours.With solvent evaporation, crude product is used ethyl acetate through the silica gel chromatography column chromatography: methyl alcohol: water (100: 12: 4) wash-out.Use a small amount of ether: sherwood oil (1: 1) recrystallization obtains 53ml(25%) 3-cyanogen methyl-2-methyl-7-(2-phenylethyl) pyrrolo-[2,3-b] pyridine.
（ 1H-NMR，500 MHz，CDCl 3）2.59（s，3H），3.34（t，2H），3.83（s，2H），4.84（t，2H），6.66（dd，1H），7.01（dd，2H），7.07（d，1H），7.23（m，3H），7.94（d，1H）.
Embodiment 4
3-methyl-7-(2-phenylethyl) pyrrolo-[2,3-b] pyridine hydrobromide salt
With 0.3g(2.3mmol) 3-methylpyrrole also [2,3-b] pyridine, 0.5g(2.7mmol) the 10ml acetonitrile solution of (2-bromotrifluoromethane) benzene refluxed 72 hours.With solvent evaporation, the solid of formation is handled with ether, uses re-crystallizing in ethyl acetate, obtains 0.2g(27%) title compound, white solid.
（ 1H-NMR，300 MHz，CDCl 3）2.35（s，3H），3.45（t，2H），5.4（t，2H），6.9-7.0（m，2H），7.1（t，1H），7.2-7.3（m，3H），7.4（dd，1H），7.55（s，1H），8.25（dd，1H）.
Embodiment 5
2-methylol-3-methyl-7-(2-phenylethyl) pyrrolo-[2,3-b] pyridine hydrobromide salt
With 0.11g(0.68mmol) 2-methylol-3-methylpyrrole also [2,3-b], 0.13g(7mmol) the 5ml acetonitrile solution of (2-bromotrifluoromethane) benzene refluxed 24 hours.With solvent evaporation.Use the silica gel chromatography column chromatography, methylene dichloride and methyl alcohol (10: 1) wash-out, the product that obtains expecting (0.3g13%).
（ 1H-NMR，500 MHz，CDCl 3），2.35（s，3H），3.4（t，2H），4.95（s，2H），5.1（t，2H），6.95-7.0（m，2H），7.05（t，1H），7.2-7.25（m，3H），7.35（dd，1H），8.15（dd，2H）.
Embodiment 6
2-chloro-3-methyl-7-(2-phenylethyl) pyrrolo-[2,3-b] pyridine
With 0.1g(0.6mmol) 2-chloro-3-methylpyrrole also [2,3-b] pyridine, 0.14g(0.78mmol) the 10ml acetonitrile solution of (2-bromotrifluoromethane) benzene refluxed 72 hours.With solvent evaporation.The solid that forms is handled filtering separation with ether and ethyl acetate.Use the silica gel chromatography column chromatography, with methylene dichloride and methyl alcohol (10: 1) wash-out, the product that obtains expecting (0.03g18%).
（ 1H-NMR，300 MHz，CDCl 3）2.3（s，3H），3.35（t，2H），4.8（t，2H），6.65（t，1H），6.95-7.0（m，2H），7.05（dd，1H），7.2-7.25（m，3H），7.8（dd，1H）.
Embodiment 7
6-amino-2,3-dimethyl-7-(2-phenylethyl) pyrrolo-[2,3-b] pyridine hydrobromide salt
With 6-amino-2, (1.0g, 6.2mmol) (1.7g, 30ml acetonitrile solution 9.3mmol) refluxed 48 hours phenethyl bromide 3-dimethyl-pyrrolo-[2,3-b] pyridine.Allow mixture cool off, leach precipitation.Use the silica gel chromatography column chromatography, with methylene dichloride and methyl alcohol (9: 1) wash-out, the product that obtains expecting (0.1g, 6%).
（ 1H-NMR，500 MHz，CDCl 3+CD 3OD）2，10（s，3H），2，25（s，3H），3，20（t，2H），4，70（t，2H），6，60（d，1H），7.10（dd，2H），7，15-7，20（m，3H），7，75（d，1H）.
Embodiment 8
2,3-dimethyl-7-phenacyl pyrrolo-[2,3-b] pyridine
With 2, the 3-dimethyl pyrrole also [2,3-b] pyridine (146mg, 1mmlo), (170mg, 1.1mmlo) 3ml acetonitrile solution refluxed 4.5 hours phenacyl chloride.Allow mixture cool off, leaching the heavy product that forms sediment, with a small amount of ice-cooled CCl 4Washing obtains 207mg(69%) pure title compound, exist with the form of hydrochloride.
（ 1H-NMR，300 MHz，DMSO-d 6），2.29（s，3H），2.42（s，3H），6.66（s，2H），7.65（m，3H），7.80（t，1H），8.11（d，2H），8.47（d，1H），8.62（d，1H），13.5（b，1H）.
Embodiment 9
3-chloro-2-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine hydrochloride
With 200ml(1.2mmol) 3-chloro-2-methylpyrrole also [2,3-b] pyridine, 204mg(11.3mmol) the 10ml CH of 2-chloro-acetophenone 3CN solution refluxed 48 hours.Reaction mixture is chilled to room temperature and stirred 1 hour.Leach precipitation, obtain 260mg(67%) 3-chloro-2-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine hydrochloride.
（ 1H-NMR，500 MHz，DMSO-d 6）2.50（s，3H），6.62（s，2H），7.68（t，2H），7.78（m，2H），8.11（d，2H），8.62（d，1H），8.70（d，1H）.
Embodiment 10
2,3-dimethyl-7-(is to bromobenzene formyl methyl) pyrrolo-[2,3-b] pyridine hydrobromide salt
Press the method for embodiment 8, with 2, the 3-dimethyl pyrrole is [2,3-b] pyridine and PBPB reaction also, makes this compound.
Productive rate: 92%.
（ 1H-NMR，300 MHz，DMSO-d 6）2，29（s，3H），2.41（s，3H），6，47（s，2H），7.63（dd，1H），7，92（m，2H），8，03（m，2H），8，43（d，1H），8，64（d，1H），12，8（b，1H）
Embodiment 11
2,3-dimethyl-7-(2-phenyl-2-hydroxyethyl) pyrrolo-[2,3-b] pyridine
With 2,3-dimethyl-7-phenacyl pyrrolo-[2,3] pyridine (120mg, 3ml MeOH solution 20mg NaBH 0.4mmol.) 4Handle twice.With solvent evaporation, residuum is distributed in 50ml CH 2Cl 2In 25ml2.5%NaOH.Tell organic layer,, use MgSO with 10ml 2MHCl washing 4Drying obtains 113mg(94% with solution evaporation) title compound, exist with hydrochloride form.
（ 1H-NMR，300 MHz，DMSO-d 6）.2.26（s，3H），2.48（s，3H），4.81（dd，1H），4.97（dd，1H），5.15（dd，1H），5.91（dd，1H），7.37（m，3H），7.53（t，1H），7.61（d，2H），8.51（t，2H），13.4（b，1H）.
Embodiment 12
3-chloro-2-methyl-7-(2-phenyl-2-hydroxyethyl) pyrrolo-[2,3-b] pyridine
To 120mg(0.37mmol) add 30mg(0.79ml in the 2ml methanol solution of 3-chloro-2-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine hydrochloride) sodium borohydride.Mixture at room temperature stirred 20 hours.With solvent evaporation, residue is distributed in 2ml 0.2M hydrochloric acid and the 2ml ethyl acetate.Add 2M sodium hydroxide and make the water layer alkalization, use twice of 2ml dichloromethane extraction.Merge organic phase, use dried over sodium sulfate, solvent evaporation.The residuum acetonitrile treatment leaches precipitation, obtains 20mg(19%) 3-chloro-2-methyl-7-(2-phenyl-2-hydroxyethyl) pyrrolo-[2,3-b] pyridine
（ 1H-NMR，500 MHz，CDCl 3）2.55（s，3H），4.76（dd，1H），4.91（dd，1H），5.32（dd，1H），6.73（dd，1H），7.20（d，1H），7.25（m，1H），7.28（m，4H），7.88（d，1H）.
Embodiment 13
2,3-dimethyl-7-(2-(is to cyano-phenyl)-the 2-hydroxyethyl) pyrrolo-[2,3-b] pyridine
With the scale of 0.4mmol, mainly the method by embodiment 11 makes 68mg(61%) pure title compound, yellow solid.
（ 1H-NMR，300 MHz，CDCl 3）.2.27（s，3H），2.51（s，3H），4.73（dd，1H），4.91（dd，1H），5.36（dd，1H），6.65（t，1H），7.03（d，1H），7.40（d，2H），7.56（d，2H），7.78（d，1H）.
Embodiment 14
2-methyl-7-phenacyl-pyrrolo-[2,3-b] pyridine hydrochlorate
With 2-methyl-pyrrolo-[2,3-b] pyridine (0.5g, 3.78mmol), phenacyl chloride (0.62g, 4.0mmol) and acetonitrile (10ml) refluxed 12 hours.Leach solid, wash with cold tetracol phenixin (2ml).Smart product obtains 0.95g(88% with chloroform/ether (1: 1) recrystallization) title compound.
（ 1H-NMR，300 MHz，DMSO-d 6）;1.25（s，3H），6.65（s，2H），6.70（s，1H），7.65（m，3H），7.80（t，1H），8.10（d，2H），8.50（d，1H），8.65（d，1H）.
Embodiment 15
2,3-dimethyl-7-(2-trifluoromethyl benzoyl methyl)-pyrrolo-[2,3-b] pyridine hydrobromide salt
With 2, and 3-dimethyl-pyrrolo-[2,3-b] pyridine (438mg, 3mmol) and 2-trifluoromethyl phenacyl bromide (798mg, acetonitrile 3mmol) (5ml) solution make title compound, productive rate 0.44g(36% according to the method for embodiment 14).
（ 1H-NMR，300 MHz，DMSO-d 6），2.45（s，3H），2.50（s，3H），6.55（s，2H），7.65（t，1H），7.95（t，1H），8.05（m，2H），8.40（d，2H），8.65（d，1H）.
Embodiment 16
3-bromo-2-methyl-7-phenacyl-pyrrolo-[2,3-b] pyridine hydrobromide salt
With 3-bromo-2-methyl-pyrrolo-[2,3-b] pyridine (250mg, 1.19mmol) and phenacyl bromide (method of pressing embodiment 14 makes the title personage, productive rate 146mg(37% for 200mg, acetonitrile 1.3mmol) (50ml) solution).
（ 1H-NMR，300 MHz，DMSO-d 6），2.5（s，3H），6.7（s，2H），7.65（t，1H），7.75（m，3H），8.1（d，2H），8.6（m，2H）.
Embodiment 17
2-chloro-3-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine hydrochloride
With 1.2g(7.2mmol) 2-chloro-3-methylpyrrole [2,3-b] pyridine and 1.3g(8.7mmol also) the 50ml acetonitrile solution of phenacyl chloride refluxed 48 hours.Cooling leaches product, and drying obtains 1.5g(65%) pure title compound.
（ 1H-NMR，300 MHz，CDCl 3）2.35（s，3H），7.0（s，2H），7.4（dd，1H），7.55（t，2H），7.65（t，1H），7.8（d，1H），8.2-8.3（m，3H）.
Embodiment 18
2-chloro-3-methyl-7-(2-phenyl-2 hydroxyethyl) pyrrolo-[2,3-b] pyridine
With 0.8g(2.5mmol) the 50ml methanol solution of 2-chloro-3-methyl-7-phenacyl-pyrrolo-[2,3-b] pyridine is chilled to 0 ℃.Use NaBH then 4Gradation is handled, and is complete until all raw material reactions.(following the tracks of reaction) with thin-layer chromatography.With the solution evaporation, residuum is distributed in methylene dichloride and the water.Tell organic layer, use Na 2SO 4Drying, solvent evaporated.Residuum is handled with ether, and filtering separation obtains 0.6g(84%) title compound, white solid.
（ 1H-NMR，300 MHz，CD 3OD）2.3（s，3H），4.5（dd，1H），4.9（dd，1H），5.25（dd，1H），6.95（t，1H），7.25-7.4（m，3H），7.5（d，2H），7.85（d，1H），8.0（d，1H）.
Embodiment 19
3-methoxyl group-2-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine hydrochloride
With 0.75g(4.6mmol) 3-methoxyl group-2-methylpyrrole [2,3-b] pyridine and 0.75g(4.8mmol also) the 50ml acetonitrile solution of phenacyl chloride refluxes 14 hours.Press the method for embodiment 17, make 0.5g(34%) expectation product.
（ 1H-NMR，300 MHz，CDCl 3）2.55（s，3H），3.95（s，3H），7.0（s，2H），7.35（t，1H），7.5（t，2H），7.6（t，1H），7.9（d，1H），8.25（d，2H），8.35（d，1H）.
Embodiment 20
2-methoxymethyl-3-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine hydrochloride
With 0.13g(0.74mmol) 2-methoxymethyl-3-methylpyrrole [2,3-b] pyridine and 0.16g(1.1mmol also) the 20ml acetonitrile solution of phenacyl chloride refluxed 15 hours.Press the method for embodiment 17, make 0.05g(20%) title compound.
（ 1H-NMR，300 MHz，CDCl 3），2.4（s，3H），3.45（s，3H），4.8（s，2H），7.05（s，2H），7.4（dd，1H），7.55（t，2H），7.65（t，1H），7.85（d，1H），8.25（d，2H），8.35（d，1H）.
Embodiment 21
2-chloro-3 methyl-7-(is to the fluorobenzoyl methyl) pyrrolo-[2,3-b] pyridine hydrochloride
With 1.2g(7.2mmol) 2-chloro-3-methylpyrrole [2,3-b] pyridine and 1.5g(8.7mmol also) the 50ml acetonitrile solution of fluorobenzoyl methyl chloride was refluxed 48 hours.Allow mixture cool off, leach solid phase prod.This solid is handled with ethyl acetate, refilters, and obtains 1.4g(57%) expectation product.
（ 1H-NMR，300 MHz，CD 3OD）2.4（s，3H），6.45（s，2H），7.4（dd，2H），7.65（dd，1H），8.25（dd，2H），8.45（cl，1H），8.7（d，1H）.
Embodiment 22
2-chloro-3-methyl-7-(2-(is to fluorophenyl)-the 2-hydroxyethyl) pyrrolo-[2,3-b] pyridine
According to the method for embodiment 18, use NaBH 4Handle 1.0g(2.8mmol) 2-chloro-3 methyl-7-(is to the fluorobenzoyl methyl) the 50ml methanol solution of pyrrolo-[2,3-b] pyridine hydrochloride, make 0.85g(99%) title compound, white solid.
（ 1H-NMR，300 MHz，CD 3OD）2.3（s，3H），4.5（dd，1H），4.9（dd，1H），5.3（dd，1H），6.95（t，1M），7.1（t，2H），7.45-7.55（m，2H），7.8（d，1H），8.0（d，1H）.
Embodiment 23
2-chloro-3-cyanogen methyl-7-phenacyl pyrrolo-[2,3-b] pyridine
With 0.66g(3.4mmol) 2-chloro-3-cyanogen methylpyrrole [2,3-b] pyridine and 0.65g(3.8mmol also) the 40ml acetonitrile solution of phenacyl bromide refluxed 20 hours.Allow mixture cool off, leach precipitated product, use the acetonitrile recrystallization.Use the silica gel chromatography column chromatography, use eluent ethyl acetate, the product that obtains expecting (0.094g, 9%).
（ 1H-NMR，300 MHz，CDCl 3）3.9（s，2H），6.15（s，2H），7.05（t，1H），7.5-7.65（m，3H），7.7（t，1H），8.1（d，2H），8.25（d，1H）.
Embodiment 24
2,3-dimethyl-7-(methylmercapto phenacyl) pyrrolo-[2,3-b] pyridine hydrobromide salt
With 0.2g(1.4mmol) 2, the 3-dimethyl pyrrole is [2,3-b] pyridine and 0.34g(1.4mmol also) acetonitrile solution of methylmercapto phenacyl bromide at room temperature stirred 4 hours.Leach precipitated product, drying obtains 0.11g(20%) title compound.
（ 1H-NMR，300 MHz，CDCl 3）2.25（s，3H），2.45（s，3H），2.6（s，3H），6.9（s，2H），7.35-7.45（m，3H），7.6（t，1H），7.75（d，1H），8.25（d，1H），8.65（d，1H）.
Embodiment 25
3-hydroxy-2-methyl-7-phenacyl pyrrolo-is [2,3-b] pyridine also
At room temperature, to 0.05g(0.16mmol) add 0.5ml(0.2mmol in the 10ml dichloromethane solution of 3-methoxyl group-2-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine) methylene dichloride (IM) solution of boron tribromide.Reaction is followed the tracks of with thin-layer chromatography.Mixture stirred 20 hours, then evaporation.Product is dissolved in 2ml methylene chloride (10/1) and the less water, and this mixture silica gel chromatography column chromatography with methylene chloride (10/1) wash-out, obtains the oily product.This oily matter is handled with ether, obtains title compound, yellow solid.
（ 1H-NMR，300 MHz，DMSO-d 6），2.35（s，3H），6.45（s，2H），7.55（bs，1H），7.7（t，2H），7.8（t，1H），8.15（d，2H），8.4（d，1H），8.6（d，1H）.
Embodiment 26
2,3-dimethyl-5-trifluoromethyl-7-phenacyl pyrrolo-[2,3-b] pyrroles
With 0.1g(0.47mmol) 2,3-dimethyl-5-trifluoromethyl-pyrrolo-[2,3-b] pyridine and 0.13g(0.84mmol) the 5ml acetonitrile solution of 2-chloro-acetophenone refluxed 48 hours.With solvent evaporation.Use the silica gel chromatography column chromatography, with methylene dichloride and methyl alcohol (100: 5) wash-out, the product that obtains expecting (0.023g 15%).
（ 1H-NMR，300 MHz，CDCl 3）2.3（s，3H），2.45（s，3H），6.15（s，2H），7.55（t，2H），7.65（t，1H），7.75（s，1H），7.95（s，1H），8.05（d，2H）.
Embodiment 27
2,3-dimethyl-7-(is right-the cyano group phenacyl) pyrrolo-[2,3-b] pyridine
With 2, the 3-dimethyl pyrrole also [2,3-b] pyridine (146ml is 1mmol) with to cyano group phenacyl bromide (248mg, 3ml CH 1.1mmol) 3CN solution refluxed 1.5 hours.Allow mixture cool off, leach solid phase prod, with a small amount of ice-cold CCl 4Washing obtains 313mg(85%) pure title compound hydrobromate.
（ 1H-NMR，300 MHz;CDCl 3）2.30（s，3H），2.50（s，3H），7.10（s，2H），7.40（dd，1H），7.68（d，2H），8.00（d，1H），8.29（d，1H），8.39（d，2H），13.6（b，1H）.
Embodiment 28
2,3-dimethyl-7-(is right-the fluorobenzoyl methyl) pyrrolo-[2,3-b] pyridine
Press the method for embodiment 27, press the scale of 1mmol, with 2, the 3-dimethyl pyrrole also [2,3-b] pyridine and the fluorobenzoyl monobromomethane made 260mg(64%) pure title compound hydrobromate.
（ 1H-NMR，300 MHz，CDCl 3），2.28（s，3H），2.56（s，3H），6.99（s，2H），7.18（m，2H），7.38（dd，1H），7.83（d，1H），8.24（d，1H），8.35（m，2H），13.8（b，1H）.
Embodiment 29
2,3-dimethyl-7-(is right-the methoxybenzoyl methyl) pyrrolo-[2,3-b] pyridine
Press the method for embodiment 27, with 2, the 3-dimethyl pyrrole also [2,3-b] pyridine (120mg, 0.82mmol) and the hydrobromate of the pure title compound of right-methoxybenzoyl monobromomethane (207mg 0.90mmol), makes 223mg(73%), faint yellow solid.
（ 1H-NMR，300 MHz，CDCl 3）2.27（s，3H），2.58（s，3H），3.88（s，3H），6.91（s，2H），7.00（m，2H），7.37（dd，1H），7.81（d，1H），8.22（d，1H），8.28（m，2H）.
Embodiment 30
2, between 3-dimethyl-7-(-the methoxybenzoyl methyl) pyrrolo-[2,3-b] pyridine
According to the method for embodiment 27, by 0.9 mole scale, with 2, the 3-dimethyl pyrrole also [2,3-b] pyridine and-the methoxybenzoyl monobromomethane, make 228mg(20%) hydrobromate of pure title compound.
（ 1H-NMR，300 MHz，CDCl 3）.2.27（s，3H），2.57（s，3H），3.91（s，3H），6.97（s，2H），7.18（dd，1H），7.37（dd，1H），7.43（t，1H），7.75（bt，1H），7.79（d，1H），7.89（d，1H），8.22（d，1H）.
Embodiment 31
2,3-dimethyl-7-(neighbour-methoxybenzoyl methyl) pyrrolo-[2,3-b] pyridine
Press the scale of 1mmol, press the method for embodiment 27, with 2,3-diformazan pyrrolo-[2,3-b] pyridine and neighbour-methoxybenzoyl monobromomethane make the hydrobromate of pure title compound, faint yellow solid, productive rate 224mg(71%).
（ 1H-NMR，300 MHz，CDCl 3）.2.26（s，3H），2.60（s，3H），4.20（s，3H），6.71（s，2H），7.04（m，1H），7.11（d，1H），7.35（dd，1H），7.59（m，1H），7.69（d，1H），7.95（dd，1H），8.20（d，1H）.
Embodiment 32
2,3-dimethyl-7-(2,4-difluoro phenacyl) pyrrolo-[2,3-b] pyridine
Press the method for embodiment 27, press the scale of 1mmol, with 2,3-dimethyl pyrrole also [2,3-b] pyridine and 2,4 difluorobenzene formyl monobromomethane makes 194mg(56%) pure title compound hydrochloride, yellow solid.
（ 1H-NMR，300 MHz，CDCl 3）2.27（s，3H），2.53（s，3H），6.76（d，2H），6.96（m overlapping signals，2H），7.34（dd，1H），7.80（d，1H），8.15（m，1H），8.22（d，1H），14.9（b，1H）.
Embodiment 33
5-chloro-3-cyano methyl-2-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine
With 5-chloro-3-cyanogen methyl-2-methyl-pyrrolo-[2,3-b] pyridine (147mg, 0.7mmol) and phenacyl bromide (142g, 7mmol) with 12ml CH 3The mixture of CN refluxed 22 hours.With the reaction mixture cooling, the title compound that collecting precipitation goes out, with a small amount of ice-cold ether washing for several times.Filtrate is handled with ether, obtains second batch, the 3rd batch pure title compound.Overall yield 257mg(91%), calculate by its hydrobromate.
（ 1H-NMR，300 MHz，DMSO-d 6）.2.53（s，3H），4.24（s，2H），6.50（s，2H），7.70（t，2H），7.83（t，1H），8.10（d，2H），8.90（d，1H），9.042（s，1H）.
Embodiment 34
2,3-dimethyl-7-(2-phenyl-2-methoxy ethyl) pyrrolo-[2,3-b] pyridine
With 2,3-dimethyl-7-(2-phenyl-2-hydroxyethyl) pyrrolo-[2,3-b] pyridines (as alkali) (266mg, 25ml anhydrous tetrahydrofuran solution degassing 1.0mmol) and with (48mg, 1.1mmol) the oil dispersion processing is 30 minutes.(62 μ l 1.0mmol), allow it react 50 minutes to add methyl-iodide.With solvent evaporation, residuum is distributed in 100ml CH 2Cl 2In the NaOH solution of 20ml5%.Organic layer MgSO 4Drying is with molten Ji evaporation.Residuum carries out chromatographic separation (silica gel, NH 3Saturated CH 2Cl 2).The fraction collection that will contain straight product, solvent evaporated stays the jelly with partial crystallization.Grind with ether, obtain 207mg(65%) pure title compound.
（ 1H-NMR，300 MHz，CDCl 3）.2.29（s，3H），2.54（s，3H），3.14（s，3H），4.41（dd，1H），4.86（dd，1H），4.99（dd，1H），6.64（t，1H），7.38（overlapping signals，6H），7.75（d，1H）.
Embodiment 35
2,3-dimethyl-7-(neighbour-oil of mirbane formyl methyl) pyrrolo-[2,3-b] pyridine
Press the method for embodiment 27, by 5 moles scale, with 2,3-dimethyl pyrrole also [2,3-b] pyridine and neighbour-oil of mirbane formyl monobromomethane makes 1.3g(66%) hydrobromate of pure title compound, yellow solid.The aftertreatment mother liquor obtains additional product.
（ 1H-NMR，300 MHz，DMSO-d 6）.2.30（s，3H），2.47（s，3H），6.38（s，2H），7.68（dd，1H），7.97（dt，1H），8.08（t，1H），8.21（dt，2H），8.37（d，1H），8.67（d，1H），12.9（b，1H）.
Embodiment 36
2,3-dimethyl-7-(neighbour-aminobenzoyl methyl) pyrrolo-[2,3-b] pyridine
With 2,3-dimethyl-7-(neighbour-oil of mirbane formyl methyl) (1.02g 2.6mmol) is dissolved in the 39ml dehydrated alcohol pyrrolo-[2,3-b] pyridine, uses SnCl 22H 2O(4.75g 21mmol) and under the dense HCL80 of 13ml ℃ handled 3 hours, allowed reaction mixture cool off, and was distributed in 500ml 2MHCl and 250ml CH then 2CL 2In.Organic layer extracts with other 150+50ml 2MHCl.Merge water, with the washing of 400ml ether.Its pH value is transferred to 12, the product of alkalization 800+400+200ml CH 2Cl 2Extract, merge organic layer, use MgSO 4Drying with solvent evaporation, obtains 340mg(46%) pure amine, the glassy yellow solid.
（ 1H-NMR，300 MHz，CDCl 3）.2.28（s，3H），2.47（s，3H），6.09（s，2H），6.21（b，2H），6.71（m，2H），6.81（t，1H），7.33（m，2H），7.82（d，1H），7.88（d，1H）.
Embodiment 37
2,3-dimethyl-7-(is right-the toluyl methyl) pyrrolo-[2,3-b] pyridine
With 2, the 3-dimethyl pyrrole also [2,3-b] pyridine (0.16g, 1.1mmol) and right-toluyl monobromomethane (0.26g, 4.5ml CH 1.2mmol) 3CN solution is warmed to backflow, and it is enough to cause that the product crystallization becomes faint yellow solid.Method by embodiment 27 is isolated precipitation, obtains 0.27g(74%) pure hydrobromate.
（ 1H-NMR，300 MHz，CDCl 3）.2.27（s，3H），2.41（s，3H），2.57（s，3H），6.94（s，2H），7.32（d，2H），7.37（dd，1H），7.80（d，1H），8.17（d，2H），8.23（d，1H），13.8（b，1H）.
Embodiment 38 and 39
(R and S)-2,3-dimethyl-7-(2-phenyl-2-hydroxyethyl) pyrrolo-[2,3-b] pyridine hydrochloride
Under 0 ℃ °, with R(-)-2-methoxyl group-2-phenylacetic acid is dissolved in 3ml SOCl 2In, be allowed to condition at then under the room temperature and reacted 4 hours.With excessive SOCl 2Evaporation, residuum is with 2,3-dimethyl-7-(2-phenyl-2-hydroxyethyl) (302ml is 1.0mmol) with (279 μ l, 20ml CH 2.0mmol) of triethylamine for the racemic mixture of pyrrolo-[2,3-b] pyridine (press embodiment 11 methods prepares) 2Cl 2Solution-treated.After at room temperature reacting 16 hours, mixture is distributed in 150ml CH 2Cl 2In 50ml 2M HCl.Collected organic layer is used 50ml 5%NaCO 3MgSO is used in the liquid washing 4Drying, evaporation then.With chromatography (silica gel, NH 3Saturated CH 2Cl 2/ ether; 1/1) separates diastereomer 1 and 2.Diastereomer 2 is through chromatography (silica gel, NH 3Saturated CH 2Cl 2) be further purified.
Foreign body object 1 and 2 productive rate are respectively: 149mg(36%) and 90mg(22%).With every kind of isomer (allosome body 1: 149mg, 0.36mmol and isomer 2: 89mg 0.21mmol) are dissolved in several ml methanol, add the LiOH(5 times of molar excess that is dissolved in a few ml water sons again), are allowed to condition under the room temperature and reacted 1 hour.With solvent evaporation, every kind of residuum is distributed in 100mlCH 2Cl 2With 50ml 5%
Na 2CO 3In.Every kind of organic layer with 50ml 2MHCl washing is once used MgSO 4Drying, evaporation obtains 100mg(92%) enantiomorph 1 and 52mg(82%) enantiomorph 2.
( 1H-NMR, 300 MHz, DMSO-d 6) .Cf. embodiment 11.
Embodiment 40
2,3-dimethyl-7-(neighbour-(2-hydroxybenzoyl) methyl) pyrrolo-[2,3-b] pyridine
With 2,3-dimethyl-7-(neighbour-methoxybenzoyl methyl) pyrrolo-[2,3-b] pyridine (75mg, 20ml CH 0.2mmol) 2Cl 2Be chilled to 0 ℃, use IMBBr 3CH 2Cl 2(200 μ l, 0.2mmol) solution-treated.React after 1 hour, reaction mixture is poured into 5% NaHCO of stirring 3Solution in.Water layer 50+10ml CH 2Cl 2Extract, merge organic layer, (use 10mlCH with egg 50ml 2MHCl washing 2Cl 2The anti-extraction 3 times).Merge organic layer, use MgSO 4Drying, evaporation.Residuum separates (silica gel, CH through chromatography 2Cl 2/ CH 3OH; 9/1), obtain 35mg(62%) pure title compound.
（ 1H-NMR，500 MHz，CDCl 3）.2.27（s，2H），2.50（s，3H），6.40（b，2H），6.93（b，1H），6.98（d，1H），7.14（t，1H），7.40（b，1H），7.65（d，1H），7.85（b，1H），8.07（d，1H）.
Embodiment 41
2,3-dimethyl-6-methylthio group-7-styroyl pyrrolo-[2,3-b] pyridine
With 2,3-dimethyl-6-methylthio group pyrrolo-[2,3-b] pyridine (100mg, 0.5mmol) 5ml CH 3The solution of CN refluxes, and (85 μ l 1.2mmol) handle, and each 24 hours, with solvent evaporation, residuum separated (silica gel, NH through chromatography with 5 parts of phenethyl bromides down 3Saturated CH 2Cl 2/ ether/sherwood oil; 5/2/3), obtain 20mg(13%) pure title compound.
（ 1H-NMR，500 MHz，CDCl 3）.2.27（s，3H），2.52（s，3H），2.53（s，3H），3.25（m，2H），5.10（m，2H），6.75（d，1H），7.25（m，1H），7.31 overlapping signals，4H），7.68（d，1H）.
Embodiment 42
2,3-dimethyl-7-styroyl-6-phenyl ethylmercapto group pyrrolo-[2,3-b] pyridine hydrochloride
With 2,3-dimethyl-6-methylthio group-pyrrolo-[2,3-b] pyridine (391mg, 9ml CH 2.0mmol) 3CN solution refluxes, and (553 μ l 4.0mmol) handle each 24 hours with 5 parts of phenethyl bromides down.With solvent evaporation, residuum separates (silica gel, NH through chromatography 3Saturated CH 2Cl 2/ ether/sherwood oil; 5/2/3).Collection contains pure product fractions, uses CH 2Cl 2Be diluted to 2 times of original volume, with 50ml 2MHCl washing.Organic layer MgSO 4Drying, evaporation obtains 221mg(26%) straight product.
( 1H-NMR, 500 MHz, CDCl 3) .2.29(s, 3H), 2.55(s, 3H), 2.90(t, 2H), 3.16(t, 2H), 3.24(m, 2H), 5.14(m, 2H), 6.92(d, 1H), 7.13(d, 2H), the 7.23(overlapped signal, 4H), and 7.29(overlapped signal 4H), 7.68(d, 1H).
Embodiment 43
2,3-dimethyl-6-methylthio group-7-phenacyl pyrrolo-[2,3-b] pyridine
With 2,3-dimethyl-6-methylthio group pyrrolo-[2,3-b] pyridine (100mg, 0.5mmol) and phenacyl chloride (804mg, 5mmol) with 3ml CH 3The mixture of CN refluxed 72 hours.With solvent evaporation, residuum separates (silica gel, CH through chromatography 2Cl 2/ CH 3OH; 59/5).Collection contains the cut of pure products, and evaporation is dissolved in 100ml CH then 2Cl 2In.Organic layer is used MgSO with 2ml 2MHCL washing 4Drying, evaporation obtains 64mg(35%) hydrochloric acid of straight product.
（ 1H-NMR of the free base，300 MHz，CDCl 3）.2.25（s，3H），2.45（s，3H），2.53（s，3H），6.62（b，2H），7.05（d，1H），7.55（m，2H），7.66（m，1H），7.85（d，1H），8.12（m，2H）.
Embodiment 44
2,3-dimethyl-5-methylthio group-7-phenacyl pyrrolo-[2,3-b] pyridine
Press the method for embodiment 43, press the scale of 0.6mmol, with 2,3-dimethyl-5-methylthio group pyrrolo-[2,3-b] pyridine (by the preparation 2, the preparation of the method for 3-dimethyl-6-methylthio group-pyrrolo-[2,3-b] pyridine) and phenacyl chloride, make 140mg(63%) hydrochloride of pure title compound.
（ 1H-NMR，500 MHz，CDCl 3）.2.26（s，3H），2.57（s，3H），2.60（s，3H），6.95（b，2H），7.60（m，2H），7.69（m，2H），8.22（s，1H），8.30（m，2H）.
Embodiment 45
2,3-dimethyl-5-methyl sulfinyl-7-phenacyl pyrrolo-[2,3-b] pyridine
With 2,3-dimethyl-5-methylthio group-7-phenacyl pyrrolo-[2,3-b] pyridine (35mg, 20ml CH 0.1mmol) 2Cl 2Solution is cooled to-20 ℃, uses 71%m-CPBA(27mg, 0.1mmol) handles 30 minutes.Use CH 2Cl 2Being adjusted to volume is 50ml, organic layer 50ml 5%Na 2CO 3Washed twice is washed once with 2MHCL and (to be used 25ml CH 2Cl 2The anti-extraction 3 times).Organic layer MgSO 4Drying, evaporation obtains 15mg(41%) pure title compound.
1The H-NMR(hydrochloride) .300 MHz, CDCl 3.2.31(s, 3H), 2.59(s, 3H), 2.95(s, 3H), 7.05(s, 2H), 7.54(t, 2H), 7.66(t, 1H), 8.16(s, 1H), 8.25(d, 2H), 8.36(s, 1H).
Embodiment 46
2,3-dimethyl-7-(neighbour-carboxyl styrene base) pyrrolo-[2,3-b] pyridine
With 2, the 3-dimethyl pyrrole also [2,3-b] pyridine (554mg, 3.8mmol) and neighbour-bromobenzene monobromoethane (1000mg, 11ml CH 3.8mmol) 3CN solution refluxed 16 hours.With solvent evaporation, residuum separates (silica gel, CH through chromatography 2Cl 2/ methyl alcohol; 9/1) obtains the 546mg enriched products.Through the chromatography separation second time (silica gel, NH 3Saturated CH 2Cl 2/ sherwood oil; 7/3), obtain pure 2,3-dimethyl-7-(neighbour-bromo styroyl) pyrrolo-[2,3-b] pyridine.
With 2,3-dimethyl-7-(neighbour-bromo styroyl) pyrrolo-[2,3-b] pyridine (249mg, the de-gassed solution of the anhydrous THF of 25ml 0.76mmol) is cooled to-78 ℃, and (576 μ l, hexane solution 0.9mmol) is handled to use the 1.6M n-Butyl Lithium then.After 3 minutes, with CO 2Gas is acutely by this solution.Allow solution be warming up to room temperature, add 1.5ml water then.With solvent evaporation, residuum separates (reverse phase silica gel post, CH through chromatography 3OH/H 2O, 6/4) obtain 51mg(23%) pure amino acid.
( 1The H-NMR hydrochloride, 300 MHz, CDCl 3) .2.22(s, 3H), 2.56(s, 3H), 3.55(t, 2H), 5.07(t, 2H), 6.86(d, 1H), 7.04(m, 1H), 7.19(m, 1H), 7.24(m, 1H), 7.83(dd, 1H), 7.91(d, 1H), 8.09(d, 1H).
Embodiment 47
5-bromo-2,3-dimethyl-7-phenacyl pyrrolo-[2,3-b] pyridine
With 5-bromo-2,3-dimethyl-pyrrolo-[2,3-b] pyridine is (by being similar to preparation 6-bromo-2,3-dimethyl-pyrrolo-[2,3-b] the method preparation of pyridine) (200mg, 0.9mmol) and phenacyl bromide (200mg, 15ml acetonitrile solution backflow 1.3mmol) 16 hours.Allow mixture cooling, leach the precipitation product, wash, obtain 243mg(72% with a small amount of ether) hydrochloride of pure title compound.
（ 1H-NMR，500 MHz，DMSO-d 6）.2.28（s，3H），2.43（s，3H），6.58（s，2H），7.68（t，2H），7.81（t，1H），8.09（d，2H），8.84（s，1H），8.95（s，1H）.
Embodiment 48
5-cyano group-2,3-dimethyl-7-phenacyl pyrrolo-[2,3-b] pyridine
With 5-cyano group-2,3-dimethyl-pyrrolo-[2,3-b] pyridine (77mg, 0.5mmol) and phenacyl chloride (650mg, 4.2mmol) with 12ml CH 3The mixture of CN refluxed 62 hours.The saturated Na of mixture 2CO 3CH is used in the solution alkalization 2Cl 2Extract.Organic layer MgSO 4Drying, evaporation.Surplus thing is surplus to separate (silica gel, CH through chromatographic column 2Cl 2/ ether; 7/3), obtain 34mg(26%) pure title compound.
（DI-MS，El at 70 eV）m/z 289（25），260（15），171（38），170（50），146（32），105（100）.
( 1H-NMR, 300 MHz, CDCl 3) 2.26(s, 3H), 2.43(s, 3H), 6.09(s, 2H), 7.54(t, 2H), 7.68(t, 1H), 7.75(d, 1H), 7.89(d, 1H), the 8.06(overlapped signal, 2H).
Embodiment 49
The preparation of 3-cyanogen methyl-2-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine hydrochloride
With 1.0g(5.8mmol) 3-cyano methyl-2-methylpyrrole [2,3-b] pyridine and 1.08g(7.0mmol also) the 50ml acetonitrile solution of phenacyl chloride refluxed 14 hours.Press the method for embodiment 17 and handle, obtain 0.5g(58%) the title compound of expectation.
（ 1H-NMR，300 MHz，DMSO-d 6），2.50（s，3H），4.25（s，2H），6.62（s，2H），7.6-7.83（m，4H），8.10（d，2H），8.56（d，1H），8.79（d，1H）.
Embodiment 50
The 3-(1-pyrazolyl) preparation of methyl-2-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine
With 30mg(0.14mmol) the 3-(1-pyrazolo) methyl-2-methylpyrrole [2,3-b] pyridine and 32mg(0.21mmol also) the 1ml acetonitrile solution of phenacyl chloride refluxed 10 hours.With solvent evaporation, crude product acetonitrile treatment, filtering separation product.Product is distributed in methylene dichloride and the saturated sodium hydrogen carbonate solution.The organic layer dried over sodium sulfate with solvent evaporation, obtains 18mg(39%) title compound.
（ 1H-NMR，300 MHz，CD 3OD），xHCl，2.60（s，3H），5.60（s，2H），6.32（t，1H），6.42（b，2H），7.5-7.8（m，6H），8.15（m，2H），8.33（d，1H），8.49（d，1H）.
Embodiment 51
3-cyanogen methyl-2-methyl-7-(4-fluorobenzoyl methyl) preparation of pyrrolo-[2,3-b] pyridine hydrochloride
With 75mg(0.44mmol) 3-cyanogen methyl-2-methylpyrrole [2,3-b] pyridine and 99mg(0.57mmol also) the 1ml acetonitrile solution of 4-fluorobenzoyl methyl chloride refluxed 48 hours.With solvent evaporation, residuum 0.4ml acetonitrile treatment, the solid after the filtration obtains 75mg(55% with 0.3ml methyl alcohol and 0.4ml acetonitrile treatment) title compound.
（ 1H-NMR，500 MHz，DMSO-d 6），2.50（s，3H），4.25（s，2H），6.62（s，2H），7.53（m，1H），7.75（m，1H），8.20（dd，2H），8.55（d，1H），8.80（d，1H）.
Embodiment 52
2,3-dimethyl-7-(2-(2-acetylamino phenyl) preparation of pyrrolo-[2,3-b] pyridine hydrobromide salt ethyl)
With 73mg(0.5mmol) 2, the 3-dimethyl pyrrole is [2,3-b] pyridine and 122mg(0.5mmol also) the 2ml acetonitrile solution of (2-bromotrifluoromethane)-monoacetylaniline refluxed 10 hours.With solvent evaporation, crude product 5ml sherwood oil: ether (1: 1) is handled, and insoluble part is handled with ether.The ether layer is separated with the oily residuum, uses the acetonitrile crystallization, obtain 15mg(7.7%) title compound.
（ 1H-NMR，300 MHz，CDCl 3），2.20（s，3H），2.38（s，3H），2.42（s，3H），3.38（t，2H），5.08（t，2H），6.48（m，1H），6.73（m，1H），7.08（m，1H），7.23-7.35（m，2H），8.09（d，1H），8.55（m，1H），10.1（s，1H）.
Embodiment 53
2,3-dimethyl-7-(2,6-difluoro phenacyl) preparation of pyrrolo-[2,3-b] pyridine hydrobromide salt
With 100mg(0.68mmol) 2, the 3-dimethyl pyrrole is [2,3-b] pyridine and 193mg(0.82mmol also) 2, the 2ml acetonitrile solution of 6-difluoro phenacyl bromide refluxed 3 hours.Press the method for embodiment 17 and handle, obtain 145mg(54%) product of expectation.
（ 1H-NMR，300 MHz，CDCl 3）.2.28（s，3H），2.62（s，3H），6.72（s，2H），7.07（m，2H），7.38（m，1H），7.58（m，1H），7.73（d，1H），8.24（d，1H）.
Embodiment 54
3-thiocyanogen-2-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine hydrochloride
With 100mg(0.53mmol) 3-thiocyanogen-2-methylpyrrole [2,3-b] pyridine and 122mg(0.79mmol also) solution of 3ml acetonitrile/dimethyl formamide (2: 1) of phenacyl chloride is 70 ℃ of heating 36 hours down.Reaction mixture is chilled to room temperature, the evaporation acetonitrile.In residuum, add the 10ml ether.Leach precipitated product,, obtain 37mg(23% with the acetonitrile washing) title compound.
（ 1H-NMR，300 MHz，DMSO-d 6）.2.65（s，3H），6.66（s，2H），7.7（m，2H），7.79-7.9（m，2H），8.11（d，2H），8.68（d，1H），8.85（d，1H）.
Embodiment 55
2-(is right-bromophenyl)-3-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine
Press the method for embodiment 8, press the scale of 1.7mmol, with 2-(right-bromophenyl)-3-methyl-pyrrolo-[2,3-b] pyridine and phenacyl bromide, make 620mg(74%) title compound.
（ 1H-NMR，500 MHz，CDCl 3）.2.55（s，3H），7.35（s，2H），7.50（t，1H），7.60（t，2H），7.65（d，2H），7.70（t，1H），7.85（m，3H），8.35（d，2H），8.45（d，1H）.
Embodiment 56
Right-[3-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine-2-yl] methyl benzoate
Press the method for embodiment 8, press the scale of 0.4mmol, with right-(the 3-methylpyrrole is [2,3-b] pyridine also)-2] yl benzoic acid ester and toluoyl monobromomethane, make 70mg(46%) title compound.
（ 1H-NMR，300 MHz，CDCl 3）.2.55（s，3H），3.90（s，3H），6.15（s，2H），6.90（t，1H），7.55（m，3H），7.65（m，1H），8.0（m，5H），8.15（m，2H）.
Embodiment 57
[right-(3-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine)-2-yl] isopropyl benzoate
Press the method for embodiment 8, press the scale of 0.2mmol,, make 25mg(30% with [right-(3-methyl-pyrrolo-[2,3-b] pyridine)-2 bases] isopropyl benzoate and phenacyl bromide) title compound.
（ 1H-NMR，300 MHz，CDCl 3）.1.35（s，3H），1.40（s，3H），2.55（s，3H），5.25（m，1H），6.15（s，2H），6.85（t，1H），7.55（m，3H），7.65（t，1H），8.05（m，5H），8.15（d，2H）.
Embodiment 58
3-methyl-2-phenyl-7-phenacyl pyrrolo-[2,3-b] pyridine
Press the method for embodiment 8, press the scale of 4mmol, use also [2,3-b] pyridine and phenacyl bromide of 3-methyl-2-phenylpyrrole, make 1.58g(98%) title compound.
( 1H-NMR, 500 MHz, CDCl 3) .2.24(s, 3H), the 7.39-7.56(signal is seriously overlapping, 8H), and 7.65(t, 1H), 7.87(d, 1H), 7.93(is overlapping, d, 2H), 8.33(is overlapping, d, 2H), 8.39(d, 1H), 13.6(b, 1H).
Embodiment 59
3-methyl-2-(is right-aminomethyl phenyl)-7-phenacyl pyrrolo-[2,3-b] pyridine
Press the method for embodiment 8, press the scale of 3mmol, with 3-methyl-2-(right-aminomethyl phenyl)-pyrrolo-[2,3-b] pyridine and phenacyl bromide, make 1.21g(96%) title compound.
( 1H-NMR, 500 MHz, CDCL 3) .2.37(s, 3H), 2.52(s, 3H), 7.29(d, 2H), 7.37(s, 2H), 7.43(dd, 1H), 7.53(t, 2H), 7.63(t, 1H), 7.81(d, 2H), 7.86(d, 1H), the 8.33(signal overlap, 3H), 13.5(b, 1H).
Embodiment 60
2-(is right-p-methoxy-phenyl)-3-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine
Press the method for embodiment 8, press the scale of 10mmol, with 2-(right-p-methoxy-phenyl)-3-methyl and pyrrolo-[2,3-b] pyridine phenacyl bromide, make 4.02g(92%) title compound.
( 1H-NMR, 300 MHz, CDCl 3) .2.50(s, 3H), 3.83(s, 3H), 7.00(d, 2H), 7.36(s, 2H), 7.42(dd, 1H), 7.53(t, 2H), 7.63(t, 1H), 7.82(d, 1H), 7.91(d, 2H), the 8.33(signal overlap, 3H), 13.5(b, 1H).
Embodiment 61
2,3-dimethyl-7-(2-phenyl-2-methoxyl group imido calabash ethyl) pyrrolo-[2,3-b] pyridine (E and Z isomer)
2,3-dimethyl-7-phenacyl pyrrolo-[2,3-b] pyridine hydrochloride (301mg, 1mmol) and methoxy amine hydrochlorate (460mg, 5mmol) with 3ml CH 3The mixture of OH and 4.5ml pyridine at room temperature reacted 5 days.With the methyl alcohol evaporation, residuum is distributed among the 150ml methylene dichloride 50ml 2M HCl.Collected organic layer is used MgSO 4Drying, evaporation, chromatography separates (silica gel, CH 2Cl 2/ CH 3OH; 92.5/7.5), obtain two isomer of 179mg and 74mg respectively.
Each isomer is dissolved in 100ml CH 2Cl 2In, with 20ml 2MHCl washing, use MgSO 4Drying, evaporation obtains 198mg(60%) isomer 1 and 70mg(21%) isomer 2.In this step, do not want to relate to stereochemistry.
( 1H-NMR isomer 1,300 MHz, CDCl 3) .2.27(s, 3H), 2.57(s, 3H), 4.10(s, 3H), 6.02(s, 2H), 6.71(t, 1H), 7.27(signal overlap, residual CHCl 3, 3H), 7.38(d, 1H), 7.70(m, 2H), 7.74(d, 1H).
( 1H-NMR isomer 2,300 MHz, CDCl 3) .2.22(s, 3H), 2.60(s, 3H), and 3.86(s.3H), 6.19(s, 2H), 7.13(t, 1H), 7.31(m, signal overlap, residual CHCl 3, 3H), 7.77(m, 2H), 7.85(d, 1H), 7.98(d, 1H).
Embodiment 62
2-chloro-3-cyanogen methyl-7-(2-phenyl-2-hydroxyethyl) pyrrolo-[2,3-b] pyridine
Use 10mg NaBH 4Handle 2-chloro-3-cyanogen methyl-7-phenacyl pyrrolo-[2,3-b] pyridine (15mg, 3ml CH 0.05mmol) 3OH solution, and be allowed to condition under the room temperature reaction 30 minutes.With solvent evaporation, residuum is distributed in CH 2Cl 2In water, tell organic layer, use Na 2SO 4Drying, evaporation.Separate with silica gel column chromatography, use the ether wash-out, the product that obtains expecting (7mg46%).
（ 1H-NMR，300 MHz，CD 3OD）：4.0（s，2H），4.55（dd，1H），4.95（s，2H），5.3（dd，1H），7.05（dd，1H），7.25-7.4（m，3H），7.5（d，2H），7.95（d，1H），8.2（d，1H）
Embodiment 63
3-(cyanogen methyl)-preparation of 5-fluoro-2-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine hydrobromide salt
Under argon gas atmosphere, with 3-(cyanogen methyl)-5-fluoro-2 methylpyrroles [2,3-b] pyridine (0.28g also, 1.5mmol) and phenacyl bromide (0.32g, 1.6mmol) refluxed 3 hours with the mixture of acetonitrile (5ml), in this course, initial solution transforms the Cheng County supernatant liquid.With the cooling of suspension ice bath, filter then, with ether (2x2ml) washing.Crystallized product obtains 0.52g(90% with hot acetonitrile recrystallization purifying) title compound.
MS m/z(relative intensity) 307(14, M+), 306(8), 279(10), 278(20), 105(100), 91(41), 77(97).
Embodiment 64
5-bromo-3-methyl-7-phenacyl-2-phenylpyrrole is [2,3-b] pyridine also
With 5-bromo-3-methyl-2-phenylpyrrole [2,3-b] pyridine (0.34g, 1.2mmol) and phenacyl bromide (0.49g 2.4mmol) refluxes with acetonitrile (20ml) and spends the night, and obtains transparent solution.Chilled solution with sodium carbonate solution (10%) alkalization, is used dichloromethane extraction, use MgSO 4Drying is filtered, and with solvent evaporation, the residuum that obtains is dissolved in the minimum ethanol.With crystallization and mother liquor one arise from place in the refrigerator several days complete to guarantee crystallization.Xln is dissolved in the hot ethanol, but spends the night in refrigerator and cooled then and carry out recrystallization, obtain 0.35g(73%) the yellow crystal body.
(free alkali, 1H-NMR, 300 MHz, CDCl 3) 2.50(s, 3H), 6.12(s, 2H), 7.29(dt, 1H, J 17.5 Hz, J 21Hz), 7.40(t, 2H, J7 Hz), 7.52-7.60(m, 3H), 7.65-7.70(m, 1H), 7.86-7.89(m, 2H), 8.01(d, 1H, J 2 Hz), 8.12(d, 2H, J 7 Hz).
Embodiment 65
3-(cyanogen methyl)-the also preparation of [2,3-b] pyridine of 7-phenacyl-2-phenylpyrrole
With 3-(cyanogen methyl) the 2-phenylpyrrole also [2,3-b] pyridine (0.35g, 1.5mmol) and acetonitrile (5ml) solution of phenacyl bromide (0.36g) refluxed 18 hours.The solid product that filtering separation obtains with ether washing, obtains pure 3-(cyanogen methyl)-7-phenacyl-2-phenylpyrrole [2,3-b] pyridine hydrobromide salt (0.46g, 70%) also.
（ 1H-NMR，300 MHz，DMSO-d 6）.4.40（s，2H），6.68（s，2H），7.56-74（m，8H），7.78-7.91（m，2H），8.12（d，2H，J 7 Hz），8.74（d，1H，J 6 Hz），9.04（d，1H，J 8 Hz）.
Embodiment 66
3-(carbamyl ylmethyl)-the also preparation of [2,3-b] pyridine of 7-phenacyl-2-phenylpyrrole
Under argon gas atmosphere, with 3-(carbamyl ylmethyl)-the 2-phenylpyrrole also [2,3-b] pyridine (0.35g, 1.4mmol) and acetonitrile (5ml) solution of phenacyl bromide (0.33g) refluxed 3 hours.The yellow suspension filtering separation that produces is got crude product (0.4g).This a spot of thick product is dissolved in the mixture of methyl alcohol (20ml) and methylene dichloride (480ml), is contained in then and dodges chromatographic column (SiO 2/ methylene dichloride: methyl alcohol=96: 4), with following eluent wash-out: a) 1000ml methyl alcohol: methylene dichloride=2.5: 97.5; B) 1000ml methyl alcohol: methylene dichloride=9: 95; C) 1000ml methyl alcohol: methylene dichloride=1: 9 obtains pure 3-(carbamyl ylmethyl)-7-phenacyl-2-phenylpyrrole [2,3-b] pyridine also, obtain with the isolated in form of its hydrobromate (0.14g, 22%).
(free alkali, 1H-NMr, 500 MHz, DMSO-d 6) 3.70(s, 2H), 6.33(s, 2H), and 6.68-7.71(t, 2H, J 7 Hz), 7.27(t, 1H, J 7.5 Hz), 7.37(t, 2H, J 7.5 Hz) and, 7.44(br s adds D 2O disappears))
），7.64（t，2H，J 8 Hz），7.77（t，1H，J 7 Hz），7.89（d，2H，J 8 Hz），8.01（d，1H，J 6 Hz），8.17（D，2H，J 7.5 Hz），8.23（d，1H，J 7.5 Hz）.
Embodiment 67
6-chloro-3-cyanogen methyl-2-methyl-7(2-phenyl-2-hydroxyethyl) pyrrolo-[2,3-b] pyridine
Press the method for embodiment 11, press the scale of 0.33mmol, with 5-chloro-3-cyanogen methyl-2-methyl-7-phenacyl pyrrolo-[2,3-b] pyridine (embodiment 33) and NaBH 4Prepared title compound, crude product separates (silica gel, CH through chromatography 2Cl 2/ CH 3OH; 96/4), obtain 45mg(42%) straight product.
( 1H-NMR, 300 MHz, CDCl 3) .2.54(s, 3H), 3.78(s, 2H), 4.67-4.90(m, 2H), and 5.30(m, 1H), the 7.32(signal just overlaps, 6H), 7.95(d, 1H).
Embodiment 68
3-cyanogen methyl-2-methyl-7-(2,4-difluoro phenacyl) preparation of pyrrolo-[2,3-b] pyridine
Press the method for embodiment 8, press the scale of 2.3mmol, with embodiment III and 2-chloro-2,4-difluoro phenyl methyl ketone makes 570mg(68%) title compound.
（ 1H-NMR，300 MHz，DMSO-d 6）.2.50（s，3H），4.25（s，2H），6.45（m，2H），7.40（dt，1H），7.65（dt，1H），7.75（t，1H），8.10（m，1H），8.55（d，1H），8.80（d，1H）.
Embodiment 69
3-cyanogen methyl-2-methyl-7-(2-methoxybenzoyl methyl) preparation of pyrrolo-[2,3-b] pyridine
Press the method for embodiment 8, press the scale of 4.2mmol, make 0.9g(54% with embodiment III and ω-bromo-2-*-methoxy acetophenone) title compound.
（ 1H-NMR，300 MHz，DMSO-d 6）.2，50（s，3H），4.10（s，3H），4.25（s，2H），6.25（s，2H），7.15（t，1H），7.40（d，1H），7.75（m，2H），7.90（dd，1H），8.60（d，1H），8.80（d，1H）.
Embodiment 70
3-cyanogen methyl-2-methyl-7-(2-(2-hydroxybenzoyl) methyl) preparation of pyrrolo-[2,3-b] pyridine
To embodiment 69 compounds (3.6g, 60ml CH 8.9mmol) 2Cl 2In the de-gassed solution, drip 1M BBr 3CH 2Cl 2(10.6mmol) solution.This solution at room temperature stirred 3 hours, poured 50ml 1M NaHCO then into 3In the solution.Water layer 100mlCH 2Cl 2Extract 3 times, merge organic layer, once with 100ml 2MHCl washing.Organic layer Na 2SO 4Drying, evaporation.Residuum CH 3The CN recrystallization obtains 2.2g(73%) title compound.
（ 1H-NMR，500 MHz，DMSO-d 6）.2.50（s，3H），4.25（s，2H），6.35（s，2H），7.00（t，1H），7.20（d，1H），7.60（t，1H），7.70（t，1H），7.85（d，1H），8.60（d，1H），8.75（d，1H）.
What following table 1 provided is the exemplary case of The compounds of this invention.
Table 1: exemplary case compound of the present invention:
Figure 921021704_IMG48
Figure 921021704_IMG49
Figure 921021704_IMG52
Figure 921021704_IMG53
The following example explanation is used to prepare the intermediate of compound that previous embodiment exemplifies.
The embodiment I
The 3-[(dimethylamino) methyl]-the also preparation of [2,3-b] pyridine of 2-methylpyrrole
With 200mg(1.5mmol) 2-methyl-pyrrolo-[2,3-b] pyridine, 200mg(2.5mmol) dimethylamine hydrochloride and 73mg(2.5mmol) the 2.5ml methanol solution of Paraformaldehyde 96 refluxed 4 days.Reaction mixture is chilled to room temperature, and decompression is down with solvent evaporation.In residuum, add 2ml water and 2ml methylene dichloride, regulate PH to 11 with the 2M sodium hydroxide solution.Organic layer washes with water once, uses dried over mgso, with solvent evaporation, obtains 0.17g(60%) title compound.
（ 1H-NMR;500 MHz，CDCl 3）.2.25（s，6H），2.50（s，3H），3.55（s，2H），7.03（dd，1H），7.92（d，1H），8.01/dd，1H）.
The embodiment II
3-[(three methylamino-s) methyl] preparation of pyrrolo-[2,3-b] pyridine
With 163mg(0.86mmol) embodiment I product and 135mg(0.95mmol) the 1ml ethanolic soln of methyl-iodide at room temperature stirred 40 hours.With solvent evaporation, obtain crude product 270mg(95%), this product can be directly used in next step reaction.
（ 1H-NMR，500 MHz，DMSO-d 6）.3.10（s，9H），3.30（s，3H），4.62（s，2H），7.12（dd，1H），8.08（d，1H），8.19（d，1H）.
The embodiment III
3-cyanogen methyl-2-methylpyrrole is the preparation of [2,3-b] pyridine also
To 270mg(0.82mmol) add 44mg(0.90mmol in the 2.5ml dimethyl formamide of embodiment II product) sodium cyanide, 100 ℃ of following heated and stirred 1.5 hours, reaction mixture is chilled to room temperature then, be distributed in then in water and the methylene dichloride.The organic layer dried over sodium sulfate with solvent evaporation, obtains 130mg(98%) title compound
（ 1H-NMR，500 MHz，CDCl 3）.2.53（s，3H），3.77（s，2H），7.12（dd，1H），7.92（dd，1H），8.27（dd，1H）.
The embodiment IV
3-chloro-2-methylpyrrole is the preparation of [2,3-b] pyridine also
Under room temperature and agitation condition, to 0.7g(5.3mmol) the 2-methylpyrrole also drips 0.8g(5.9mmol in the 2.5ml glacial acetic acid solution of [2,3-b] pyridine) SULPHURYL CHLORIDE.Reaction mixture was stirred 1 hour.With solvent evaporation, residuum is distributed in methylene dichloride and the saturated sodium bicarbonate solution.The organic layer dried over sodium sulfate, with solvent evaporation, the residuum ether: ethyl acetate (5: 1) crystallization obtains 0.45g(51%) title compound.
（ 1H-NMR，500 MHz，CDCl 3）.2.50（s，3H），7.12（dd，1H），7.84（dd，1H），8.25（dd，1H）.
The embodiment V
2-methylol-3-methylpyrrole is the preparation of [2,3-b] pyridine also
In 3ml acetate, handle 2 with the bromine of equimolar amount, the 3-dimethyl pyrrole also [2,3-b] pyridine (0.2g 0.0014mol), generates yellow mercury oxide after 5 minutes.Leach solid, used the 3ml water treatment then 60 minutes, with mixture furnishing alkalescence, use dichloromethane extraction with supercarbonate, dry organic layer, oily product (0.12g, 53%) is isolated in evaporation.
（ 1H-NMR，300 MHz，CDCl 3）.2.2（s，3H），4.7（s，2H），7.0（dd，1H），7.8（dd，1H），8.25（dd，1H）.
The embodiment VI
2-chloro-3-methylpyrrole is the preparation of [2,3-b] pyridine also
Under 0 ℃, in 2ml acetate, with the SULPHURYL CHLORIDE of equimolar amount handle the 3-methylpyrrole also [2,3-b] pyridine (0.5g, 0.0038mol) 5 minutes, allow mixture be warming up to room temperature, stirred then 5 minutes.After the evaporation residuum is dissolved in the methylene dichloride, handles with supercarbonate then.Tell organic layer, drying, decompression removes down and desolvates.Use the silica gel chromatography chromatographic separation, use eluent ethyl acetate, the product that obtains expecting (0.18g, 29%).
（ 1H-NMR，300 MHz，CDCl 3）.2.25（s，3H），7.05（dd，1H），7.75（dd，1H），8.25（dd，1H）.
The embodiment VII
2.3-the preparation of dimethyl-5-difluoromethyl pyrrolo-[2,3-b] pyridine
(10g, 0.055mol) (2.7g, 0.055mol) mixture with the 35ml n-propyl alcohol refluxed 2 hours, at room temperature stirred then 20 hours with a hydrazine hydrate with 2-chloro-5-5-flumethiazine.In solution, add 4.35g(0.06mol) methyl ethyl ketone, reflux mixture 30 minutes then.After the removal of solvent under reduced pressure, residuum is distributed in methylene dichloride and the bicarbonate solution.Organic layer Na 2SO 4Drying, evaporation.Residuum is dissolved in the 80ml glycol ether, refluxed then 5 hours.Reaction mixture is poured in the frozen water, used CH 2Cl 2Extract.Tell organic layer, use Na 2SO 4Drying, evaporation.Residuum is handled with warm sherwood oil (60-80 ℃), and pen goes out sherwood oil, evaporation, and with silica gel chromatography chromatographic separation twice, with (1) methylene chloride, (2) eluent ethyl acetate, the product that obtains expecting (0.2g, 1.7%).
（ 1H-NMR，300 MHz，CDCl 3）.2.3（s，3H），2.45（s，3H），8.0（s，1H），8.5（s，1H）.
The embodiment VIII
3-methoxyl group-2-methylpyrrole is the preparation of [2,3-b] pyridine also
With 7.4g(68mmol) 2-hydrazino pyridine and 6.0g(68mmol) the 50ml ethanolic soln of methoxy acetone refluxed 1 hour.Removal of solvent under reduced pressure.To obtain oily matter and be dissolved in the glycol ether, reflux then 1.5 hours.Allow mixture cool off, pour in the frozen water then.Use dichloromethane extraction, obtain the dark oil residuum, this residuum is handled with boiling petroleum ether (60-80 ℃).After pen goes out solvent, allow its cooling, leach precipitated product, obtain 4.5g(41%) pure title compound, yellow solid.
（ 1H-NMR，300 MHz，CDCl 3）.2.45（s，3H），3.9（s，3H），7.0（t，1H），7.85（d，1H），8.15（d，1H）.
The embodiment IX
2-chloro-3-cyanogen methylpyrrole is [2,3-b] pyridine also
Under 0 ℃, in 5ml acetate, handle also [2,3-b] pyridine (1.55g, 0.098mol) 5 minutes of 3-cyanogen methylpyrrole with the SULPHURYL CHLORIDE of equimolar amount.Allow mixture be warming up to room temperature, stirred 5 minutes.After the evaporation, residuum is dissolved in the methylene dichloride, handles with supercarbonate.Tell organic layer, use Na 2SO 4Drying, removal of solvent under reduced pressure.Separate with silica gel chromatography, use eluent ethyl acetate, the product that obtains expecting (0.4g, 21%).
（ 1H-NMR，500 MHz，CDCl 3）.3.85（s，2H），7.2（t，1H），8.05（d，1H），8.4（d，1H）.
The embodiment X
2-methoxymethyl-3-methylpyrrole is [2,3-b] pyridine also
In 7ml acetate, handle 2 with the bromine of equimolar amount, the 3-dimethyl pyrrole is [2,3-b] pyridine 0.5g(0.0034mol also), generate yellow mercury oxide after 5 minutes.Leach solid, handle with 20ml methyl alcohol.Mixture was refluxed 30 minutes.Evaporation then.Residuum is distributed in methylene dichloride and the bicarbonate solution.Tell organic layer, use Na 2SO 4Drying, evaporation.Residuum is handled with ebullient sherwood oil (60-80 ℃), and pen goes out sherwood oil, cooling.Leach precipitated product, obtain 0.13g(22%), white solid.
（ 1H-NMR，300 MHz，CDCl 3）.2.3（s，3H），3.4（s，3H），4.65（s，2H），7.05（dd，1H），7.85（d，1H），8.3（d，1H）.
The embodiment XI
6-bromo-2, the preparation of 3-dimethyl-pyrrolo-[2,3-b] pyridine
With 2, (47.4g, 0.3mol) (97.2ml, 2.0mol) mixture with the 400ml propyl alcohol refluxed 19 hours the 6-dibromo pyridine with a hydrazine hydrate.With solvent evaporation, residuum is dissolved among the 1000mlC H Cl.Organic layer 500ml 5%Na 2CO 3Washing (extracting with the 500+250+250ml methylene dichloride is counter) merges organic layer, uses MgSO 4Drying, evaporation.Residuum obtains 30.0g2-bromo-6-hydrazino pyridine with 100ml dehydrated alcohol recrystallization.Handle mother liquor, the 2.5g product of getting back.Productive rate 32.5(87%).
Reflux down, (20ml, (30.5g, dehydrated alcohol 0.17mol) are supernatant liquid 1 hours 0.22mol) to handle 2-bromo-6-hydrazino pyridine with methyl ethyl ketone.Allow reaction mixture cool off, and then handle, until all raw material disappearances (according to thin-layer chromatography) with methyl ethyl ketone (10+3+1ml).Reaction mixture is dissolved in the 150ml glycol ether 70 ℃ of following reduction vaporization ethanol.With the rest solution degasification, reflux is 22 hours then.With the reaction mixture cooling, be distributed in 1250ml CH then 2Cl 2With (use 250mlCH among the 1000ml 2M HCl 2Cl 2The anti-extraction.) organic layer further uses 500ml 2M HCl and 500ml H 2MgSO is used in the O washing 4Drying, evaporation.Chromatography separates (silica gel, CH 2Cl 2/ ether; 95/5) obtains 6g 6-bromo-2,3-dimethyl-pyrrolo-[2,3-b] pyridine.With 120ml dehydrated alcohol recrystallization, get 4.2g(11%) product.
（ 1H-NMR，500 MHz，CDCl 3）2.19（s，3H），2.42（s，3H），7.16（d，1H），7.59（d，1H），9.12（b，1H）.
The embodiment XII
2, the preparation of 3-dimethyl-6-methylthio group pyrrolo-[2,3-b] pyridine
With 6-bromo-2, (225mg, the de-gassed solution of the anhydrous THF of 25ml 1.0mmol) is chilled to-78 ℃ to 3-dimethyl-pyrrolo-[2,3-b] pyridine, uses hexane (1.5ml, 2.4mmol) solution-treated of 1.6M n-Butyl Lithium then.Reaction mixture is warming up to 0 ℃ and uses dimethyl disulphide (444 μ l, 5mmol) separation lithiumation thing then.React after 5 minutes, add 1.5mlH 2O evaporates THF then.Residuum is dissolved in 100ml CH 2Cl 250ml5%NaHCO 3, 50ml 2N HCl(25ml CH 2Cl 2Instead extract twice) and 50ml 5% NaHCO 3Washing.Organic layer MgSO 4Drying, evaporation obtains 160mg(83%) pure 2,3-dimethyl-6-methylthio group-pyrrolo-[2,3-b] pyridine.
（ 1H-NMR，500 MHz，CDCl 3）2.17（d，3H），2.36（s，3H），2.60（s，3H），6.94（d，1H），7.58（d，1H），8.42（b，1H）.
Embodiment X III
3-thiocyanogen-2-methylpyrrole is the preparation of [2,3-b] pyridine also
Under 5 ℃, to 300mg(2.36mmol) 2-methylpyrrole [2,3-b] pyridine and 920mg(11.3mmol also) in the 5ml acetic acid solution of Sodium Thiocyanate 99, add 450mg(2.8mmol) the 1ml acetic acid solution of bromine.Reaction mixture stirred 30 minutes down at 5 ℃, at room temperature stirred subsequently 16 hours.Leach solid, in filtrate, add 20ml water.Leach precipitated product, wash with water, obtain 160mf(37%) title compound.
（ 1H-NMR 300 MHz DMSO-d 6）.2.55（s，3H），7.22（dd，1H），7.97（dd，1H），8.28（dd，1H），12.5（s，1H）.
Embodiment X IV
The 3-(1-pyrazolyl) methyl-2-methylpyrrole [2,3-b] pyridine also
To 95mg(0.29mmol) 3-[(three methylamino-s) methyl] in the 1.0ml dimethyl formamide solution of pyrrolo-[2,3-b] pyridine, add 24mg(0.35mmol) pyrazoles, 100 ℃ of following heated and stirred 1.5 hours.Reaction mixture is chilled to room temperature, is distributed in then in water and the methylene dichloride.The organic layer dried over sodium sulfate with solvent evaporation, obtains 30mg(48%) title compound.
1H NMR（300 MHz，CDCl 3）.2.55（s，3H），5.45（s，2H），6.20（m，1H），7.03（m，1H），7.52（m，1H），7.62（d，1H），7.7（m，1H），8.21（m，1H）.
Embodiment X V
5-cyano group-2,3-dimethyl-pyrrolo-[2,3-b] pyridine
In autoclave, add 5-bromo-2, the 3-dimethyl pyrrole also [2,3-b] pyridine (by being similar to preparation 6-bromo-2, the 3-dimethyl pyrrole is the method preparation of [2,3-b] pyridine also) (247mg, 1.1mmol) and CuCN(135mg, 1.5mmol).The pyridine that adds capacity in mixture is heated to 220 ℃ then and kept 12 hours.After the cooling, pour reaction mixture into FeCl 36H 2O(0.9g), dense HCl(0.5ml) and in the mixture of water 10ml.With mixture heating up to 80 ℃, kept 1 hour, use CH 2Cl 2Extract.Organic layer is used MgSO with 2M HCl washing four times 4Drying, evaporation obtains 77mg(40%) 5-cyano group-2,3-dimethyl-pyrrolo-[2,3-b] pyridine.
（ 1H-NMR，300 MHz，DMSO-d 6）2.18（s，3H），2.35（s，3H），8.32（d，1H），8.45（d，1H）.
Embodiment X VI
5-chloro-3-cyanogen methyl-2-methylpyrrole [2,3-b] pyridine
With 2, (10.7g, 0.07mol) (34.0ml, 0.7mol) mixture with the 140ml propyl alcohol refluxed 17 hours the 5-dichloropyridine with a hydrazine hydrate.With solvent evaporation, residuum is dissolved in 500mlCH 2Cl 2In.Organic layer 200ml 5%NaHCO 3Solution washing (is used 100ml CH 2Cl 2The anti-extraction), use MgSO 4Drying, evaporation.Residuum obtains 4.7g5-chloro-2-hydrazino pyridine with 17ml dehydrated alcohol recrystallization.Handle the mother liquor 0.1g product of getting back.Altogether product 4.8g(48%).
With 5-chloro-2-hydrazino pyridine (4.9g, 34mmol) and-(3.5g's (methylthio group) acetone 34mmol) refluxes with the mixture heating up of 1 dehydrated alcohol.With the reaction mixture cooling, be dissolved in the 30ml glycol ether.At 70 ℃ of following pressure reducing and steaming ethanol.With the rest solution degassing, reflux is 1.5 hours then.With the reaction mixture cooling, be dissolved in 500mlCH then 2Cl 2In.Organic layer 400mlH 2O washed twice (every part of 100ml CH 2Cl 2The anti-extraction), use MgSO 4Drying, evaporation.The residuum filtered through silica gel is used CH 2Cl 2Wash-out.Collect product section, add small amount of ethanol, boil off CH then 2Cl 2The 5-chloro-2-methyl of collecting precipitation-3-methylthio group-pyrrolo-[2,3-b] pyridine is used a small amount of petroleum ether, obtains 1.5g(20%) straight product.Handle mother liquor 1.0g(14% again) product.
With 5-chloro-2-methyl-3-methylthio group pyrrolo-[2,3-b] and pyridine (1.1g, 45ml1 5.0mmol), the de-gassed solution of 4-dioxan are heated to 70 ℃, handle several times with a small amount of Raney nickel then, up to raw material (GC-MS tracking) (total reaction time: 48 hours) that all disappear.Leach catalyzer, with several parts of 5%Na 2CO 3Washing.Go out pure 5-chloro-2-methyl-pyrrolo-[2,3-b] pyridine white precipitate in the filtrate, collect it.Behind the evaporated filtrate, obtain second batch of product, it is dissolved among the 2M HCl, use Na 2CO 3Alkalizing solution slowly.Produce 0.6g(74%) product.
With 5-chloro-2-methyl-pyrrolo-[2,3-b] pyridine (514mg, 3.1mmol), Paraformaldehyde 96 (102mg, 3.4mmol) and the dimethyl amine hydrochloride (227mg 3.4mmol) refluxed 1.5 hours with the mixture of 12ml butanols.With most of solvent evaporation, the remaining aqueous residuum is handled with ice-cold ether.Collecting precipitation, drying obtains 707mg(93%) 1: 1 mixture of 5-chloro-3-dimethylamino methyl-2-methyl-pyrrolo-[2,3-b] pyridine and corresponding hydrochloride.
Use dense HCl(1.16ml, 140mmol) handle 1: 1 mixture of 5-chloro-3-dimethylamino methyl-2-methyl-pyrrolo-[2,3-b] pyridine and corresponding hydrochloride, each 12 hours, until all raw material disappearances (analyzing) according to DI-MS.Reaction mixture is dissolved in 200ml 5%Na 2CO 3In the solution, use 200mlCH 2Cl 2Extract twice.Merge organic layer, use MgSO 4Drying, evaporation obtains 147mg(26%) pure 5-chloro-3-cyanogen methyl-2-methyl-pyrrolo-[2,3-b] pyridine.
（ 1H-NMR，500 MHz，CDCl 3）2.51（s，3H），3.72（s，2H），7.87（d，1H），8.21（d，1H），9.16（b，1H）.
Embodiment X VII
2-(is right-bromophenyl)-3-methyl-pyrrolo-[2,3-b] pyridine
(11.1g, 0.01mol) and to monobromo propionyl benzene (25g 0.12mol) refluxed 12 hours with 85ml95% alcoholic acid mixture with the 2-hydrazino pyridine.With solvent evaporation, obtain quantitative corresponding hydrazone.
（DI-ms，EI at 70 ev）m/z 303（5），274（70），183（100），155（65）.
Residuum is dissolved in the 100ml glycol ether, the degassing, vigorous reflux is 6 hours in nitrogen atmosphere, allows reaction mixture cool off, and pours 700ml H then into 2Among the O.The collecting precipitation product is used ethyl alcohol recrystallization, obtains 6.48g(22%) expectation product.
（ 1H-NMR，300 MHz，CDCl 3）.2.45（s，3H），7.10（dd，1H），7.50（d，2H），7.65（d，2H），7.90（dd，1H），8.25（d，1H）.
Embodiment X VIII
2-(is right-carboxyl phenyl)-3-methyl-pyrrolo-[2,3-b] pyridine
With 2-(right-bromophenyl)-3-methyl-pyrrolo-[2,3-b] pyridine (1g 3.5mmol) is dissolved among the anhydrous THF of 200ml, the degassing, be chilled to-78 ℃ then, and the dropping n-Butyl Lithium (5,19ml, 8.4mmol), allow mixture be warming up to room temperature then, logical CO in solution 2Gas 10 minutes.
Destroy excessive n-Butyl Lithium with less water, with solvent evaporation, residuum is distributed in 100ml CH 2Cl 2With 100ml 5%Na 2CO 3In the solution.Water layer is acidified to PH=2 with 2MHCl.Leach precipitated product, drying obtains 0.28g(44%) title compound.
（ 1H-NMR，300 MHz，D 2O）.2.35（s，3H），7.15（bs，1H），7.65（d，2H），7.95（m，3H），8.20（bs，1H）.
Embodiment X IX
Right-[3-methyl-pyrrolo-[2,3-b] pyridine-2] base-Benzoyl chloride
Under 0 ℃, with 2-(right-carboxyl phenyl)-(1g 4mmol) is dissolved in the 20ml thionyl chloride 3-methyl-pyrrolo-[2,3-b] pyridine.Allow solution at room temperature react 2 hours.With solvent evaporation.Residuum CH 2Cl 2Evaporation twice to remove excessive thionyl chloride, obtains quantitative title compound.
（ 1H-NMR，300 MHz，CDCl 3）.2.50（s，3H），7.40（t，1H），7.80（d，2H），8.20（m，3H），8.40（d，1H）.
The embodiment XX
[right-(3-methyl-pyrrolo-[2,3-b] pyridine 2) and base] methyl benzoate
Will be to [3-methyl-pyrrolo-[2,3-b] pyridine-2] basic Benzoyl chloride (0.41g, 1.5mmol) chromatogram chromatographic separation (CH on silicagel column 2Cl 2: CH 3OH, 95: 5), obtain 0.28g(69%) and title compound.
（ 1H-NMR，300 MHz，CDCl 3）.2.50（s，3H），3.95（s，3H），7.10（dd，1H），7.75（d，2H），7.95（d，1H），8.15（d，2H），8.20（d，1H）.
Embodiment X XI
[to (3-methyl-pyrrolo-[2,3-b] pyridine)-2] yl benzoic acid isopropyl ester
With right-[3-methyl-pyrrolo-[2,3-b] pyridine-2] (1.1g 4mmol) is dissolved in 20ml CH to basic Benzoyl chloride 2Cl 3In.Add then the 2-propyl alcohol (1.20ml, 20mmol) and triethylamine (0.4g 4mmol), allows mixture at room temperature react 24 hours.With solvent evaporation, residuum chromatography purification (silica gel, CH 2Cl 2: CH 3OH, 97: 3), obtain 102mg(9%) and title compound.
（ 1H-NMR，300 MHz，CDCl 3）.1.40（s，3H），1.45（s，3H），2.55（s，3H），5.35（m，1H），7.10（dd，1H）7.85（d，2H），7.95（d，1H），8.20（m，3H）.
Embodiment X XII
3-methyl-2-phenylpyrrole is [2,3-b] pyridine also
(21.8g, 20mmol) (29.3g 22mmol) refluxed 3 hours with 160ml95% alcoholic acid mixture with propionyl benzene with the 1-hydrazino pyridine.With solvent evaporation, obtain quantitative corresponding hydrazone.
（DI-MS，El at 70 eV）m/z 225（8），196（100），148（15）.
Residuum is dissolved in the 200ml glycol ether, the degassing, vigorous reflux is 4 hours under nitrogen atmosphere.Allow the reaction mixture cool overnight, pour 1000mlH then into 2Among the O.The collecting precipitation product is used ethyl alcohol recrystallization, obtains 18.4g(44%) expectation product.
（ 1H-NMR，500 MHz，CDCl 3）.2.49（s，3H），7.07（dd，1H），7.42（t，1H），7.55（t，2H），7.73（d，2H），7.91（d，1H），8.21（d，1H），11.38（b，1H）.
Embodiment XX III
3-methyl-2-(is right-aminomethyl phenyl) and pyrrolo-[2,3-b] pyridine
Press the method for embodiment X XII, press the scale of 10mmol, make title compound, productive rate 0.9g(4%).
(DI-MS, El, 70 eV, hydrazone) m/z 239(5), 210(100), 148(12).
（ 1H-NMR，500 MHz，CDCl 3）.2.45（s，3H），2.47（s，3H），7.08（dd，1H），7.34（d，2H），7.59（d，2H），7.89（dd，1H），8.23（dd，1H），10.6（b，1H）.
Embodiment XX IV
2-(is right-p-methoxy-phenyl)-3-methyl-pyrrolo-[2,3-b] pyridine
Press the method for embodiment X XII, press the scale of 20mmol, make title compound, productive rate 6.0g(13%)
(DI-MS, El, 70 eV, hydrazone) m/z 255(8), 226(100), 211(12).
（ 1H-NMR，500 MHz，CDCl 3）.2.45（s，3H），3.90（s，3H），7.06（m，3H），7.63（d，2H），7.87（dd，1H），8.12（dd，1H），10.7（b，1H）.
Embodiment XX V
The preparation of 5-fluoro-2-hydrazino pyridine
In polytetrafluoroethylcontainer container, with argon gas feed 2-chloro-5-fluorine pyridine (5g, 0.038mol) and a hydrazine hydrate (15ml, 0.32mol) with the mixture of n-propyl alcohol (40ml) in, place stainless steel cylinder then, 200 ℃ of heating 19 hours (magnetic stirring) down.With solvent evaporation, remove an excessive hydrazine hydrate under the vacuum, obtain solid residue (5.9g), it is dissolved in the sodium hydrogen carbonate solution (5%), with 6 * 50ml ethyl acetate extraction.The united extraction thing is used anhydrous Na 2SO 4Drying is filtered, and evaporation obtains oily matter (2.9g), and this oily is difficult to purifying, thereby is directly used in next step reaction.This crude product contains the tertiary mixture of product, 2-chloro-5-hydrazino pyridine and the 5-hydrazino pyridine of expectation.
（ 1H-NMR，500 MHz，DMSO-d 6）.6.73（dd，1H，J 19 Hz，J 23.5 Hz），7.41（td，1H，J 19.5 Hz，J 23 Hz），7.95（d，1H，J 13 Hz）
Embodiment XX VI
The preparation of 5-fluoro-2-methyl-3-methylthio group pyrrolo-[2,3-b] pyridine
(6.04g, (99.5%, 15ml) vlil two or three minutes, reduction vaporization obtains oily matter (11.5g) to ethanol 0.058mol) then with 50 fluoro-2-hydrazino pyridine crude products (6.7g, at most 0.053mol) and (alpha-methylmercapto) acetone.Under argon gas atmosphere, with glycol ether (50ml) vlil of this oily matter 8 hours.Reaction mixture is chilled to room temperature, and (10%, 200ml) dilution is with ether (200ml) and methylene dichloride (2 * 200ml) extractions with sodium carbonate solution.United extraction liquid is used anhydrous Na 2SO 4Drying, vacuum-evaporation obtains oily matter, and this oily matter chromatogram is dodged chromatographic separation (SiO 2/ CH 3OH: CH 2Cl 20,1 and 2%), obtains title compound (0.22g, 2%, two step).
MS m/z(relative intensity) 196(100, M +), 181(100), 137(58).
Embodiment XX VII
5-fluoro-2-methylpyrrole is the preparation of [2,3-b] pyridine also
With Raney nickel (the 10g alloy that wets, Aldrich W2, with the washing of 10 * 50ml deionized water and 5 * 40ml diox) be suspended in 5-fluoro-2-methyl-3-methylthio group pyrroles and merge [2,3-b] pyridine (0.5g, 2.5mmol in) De diox (50ml) solution, reaction mixture stirred 43 hours under hydrogen atmosphere.Add Raney nickel (5g, wet) again, continuously stirring is spent weekend (69 hours) under hydrogen atmosphere then.Use diatomite filtration, evaporation obtains the 0.24g crude product.Extract Raney nickel with Soxhlet, the crude product of getting back (0.48g).Crude product is not purified to be directly used in next step reaction.
MS m/z(relative intensity) 150(75, M +), 149(100), 122(15).
Embodiment XX VIII
3-(cyanogen methyl)-5-fluoro-2-methylpyrrole [2,3-b] pyridine also
Under argon gas atmosphere and agitation condition, with Manny phase reagent [0.8ml presses Liebigs(1971) Ann.Chem, 743,95-111 method preparation) add precooling (78 ℃) 5-fluoro-2-methylpyrrole also [2,3-b] pyridine (0.33g, 2.2mmol) in.The flask that will contain reaction mixture then places ice bath, continues to stir, up to forming white suspension.Ice cube melts in 2 hours, allows the warming-in-water of its generation to room temperature.After 24 hours, nearly all suspended substance dissolving.With the cooling of reaction mixture ice bath, with deionized water (8ml) dilution, (2 * 5ml) extract, to remove some remaining raw materials and by product (may be corresponding Manny phase dipolymer) with ether.With sodium cyanide (1.08g 0.022mol) adds water, and we think that water contains the 3-(dimethylamino methyl)-5-fluoro-2-methylpyrrole [2,3-b] pyridine also, the solution that obtains was refluxed 2 hours, system becomes suspension, filtering separation.Dodge chromatography purification (SiO with chromatogram 2/ CH 2Cl 2: CH 3OH 19: 1), obtain 0.28g(67%, 2 steps) 3-(cyanogen methyl)-5-fluoro-2-methylpyrrole [2,3-b] pyridine also.
MS m/z(relative abundance) 189(100, M +), 188(97), 174(83), 163(55), 162(35), 147(18), 121(19).
Embodiment XX IX
The preparation of 5-bromo-2-hydrazino pyridine
By the method for preparing 5-chloro-2-hydrazino pyridine, with 2, the 5-dibromo pyridine is a raw material, makes title compound.
（ 1H-NMR，300 MHz，CDCl 3）.3.78（br s，2H），5.83（br s，1H），6.65（d，1H，J 9 Hz），7.54（dd，1H，J 19 Hz，J 22.5 Hz），8.14（d，1H，J 2.5）.
The embodiment XXX
5-bromo-3-methyl-2-phenylpyrrole is the preparation of [2,3-b] pyridine also
(15.6g 0.083mol) heats (vapor bath) 30 minutes with the abnormal benzene of propionyl (11.1ml) down at 90 ℃ with 5-bromo-2-hydrazino pyridine.Add toluene (100ml) then, the solution that obtains was refluxed 2 hours, remove by component distillation (Dean Stark equipment) and anhydrate.With solvent evaporation, obtain the 26.4g crude product, we think the hydrazone expected.Crude product hydrazone (3.02g) is dissolved in the glycol ether (30ml), in argon gas atmosphere, 245 ℃ of following reflux 24 hours.Reaction mixture is poured in the trash ice, used dichloromethane extraction.Use MgSO 4Drying with solvent evaporation, gets pitch shape residuum and develops with ether, obtains 0.84g(30%) filbert, hemicrystalline product.
（ 1H-NMR，300 MHz，DMSO-d 6）.2.50（s，3H），7.41（t，1H，J 7 Hz），7.52（t，2H，J 7 Hz），7.71（d，2H，J 7 Hz），8.23（m，2H）.
Embodiment XX XI
The 2-phenylpyrrole is the preparation of [2,3-b] pyridine also
(28.2g, 0.24mol) (25.7g, mixture 0.24mol) heated 0.5 hour with steam bath with the 2-hydrazino pyridine with acetylbenzene.Add toluene (200ml), obtain solution and refluxed 2 hours, component distillation (Dean Stark equipment) removes and anhydrates.Evaporating solvent obtains the 55.4g crude product, and we think the hydrazone expected.With crude product hydrazone distillation purifying (Wei Geluo device), obtain yellow oil (38.4g, 77%).(18g 0.085mol) is dissolved in the Tetraglycol 99 (180ml), refluxes 6 hours under argon gas atmosphere with fresh hydrazone.With the reaction mixture cooling, under the agitation condition,, two-phase is separated with ether (250ml) and water (250ml) dilution, water extracts with ether (200ml) is anti-.The combined ether phase is used anhydrous sodium sulfate drying, filters, evaporates, and obtains dark oil thing (14.9g), and this oily matter further distills, dodges chromatography (SiO through chromatogram with Kugel-rohr 2/ CH 3OH: CH 2Cl 2, do not contain methyl alcohol before this, progressively increase methyl alcohol then to increase flowability) and recrystallization (methylene dichloride), obtain also [2,3-b] pyridine of the pure 2-phenylpyrrole of 1.5g.
MS m/z（. ）195（15，M+1），194（100，M +），193（20），166（12），139（10），97（21），91（18），84（11）.
Embodiment XX XII
3-(cyanogen methyl)-the also preparation of [2,3-b] pyridine of 2-phenylpyrrole
With formalin (36%, 1.7ml) cooling (ice bath), add then acetate (3ml) and dimethylamine agueous solution (40%, 2.5ml).This solution was kept 30 minutes down at 0 ℃, then under argon gas atmosphere, (78 ℃) that its part (2.6ml) is transferred to precooling contain the 2-phenylpyrrole also in the flask of [2,3-b] pyridine, temperature becomes 0 ℃ (ice bath) after 5 minutes, is allowed to condition at then in 2 hours to reach room temperature.The suspension that obtains was stirred 110 hours.Be chilled to 0 ℃ again, stir adding deionized water (25ml) and ether (7ml) down, the two-phase that produces is separated.Discard organic phase, because we think that it contains some unreacted raw materials and this Manny phase dipolymer.
Sodium cyanide (3.6g) is added aqueous phase, and we think that water contains the 3-(dimethylamino methyl)-2-phenylpyrrole [2,3-b] pyridine also.The mixture backflow after 3 hours, any variation (SiO do not occurred on thin-layer chromatography 2/ CH 2Cl 2: CH 3OH 19: 1), this shows that mannich base does not have variation.From reaction mixture, reclaim the 3-(dimethylamino methyl with following method)-2-phenylpyridine also [2,3-b] pyridine: add entry (25ml), leach solid matter, filtrate is used dichloromethane extraction, with methylene dichloride repetitive scrubbing filter cake, therefrom isolate most of mannich base.The merging washings (3 * 100ml), contain a small amount of soluble mannich base in this washings, drying, evaporation is up to precipitation just occurring.This saturated solution is contained in dodges chromatography (SiO on the chromatographic column 2/ CH 2Cl 2, at CH 2Cl 2: CH 3OH prepares in 9: 1), with methylene dichloride, methanol mixture (500ml CH 2Cl 2; 500ml CH 3OH: CH 2Cl 22: 98; 500ml CH 3OH: CH 2Cl 24: 96; 500ml CH 3OH: CH 2Cl 28: 92) wash-out, separate the 3-(dimethylamino methyl obtain reclaiming)-2-phenylpyrrole [2,3-b] pyridine (1.26g, 68%) also.
(1.94g, (1.25g is in methyl alcohol 5mmol) (10ml) solution 0.012mol) to add the mannich base that reclaims with iodoethane.This solution stirred 1.5 hours under argon gas atmosphere.Add potassium cyanide (0.18g, deionized water 0.012mol) (1.8ml) solution then.With reaction mixture reflux 1 hour.With solvent evaporation, residuum water (10ml) dilution that obtains, (3 * 10ml) extract, and united extraction liquid is used MgSO with ethyl acetate 4Drying, vacuum-evaporation, the solid that obtains dodges chromatography purification (SiO with chromatogram 2/ CH 2Cl 2, the amount that increases methyl alcohol is gradually carried out wash-out, above seeing), obtain pure title compound (0.85g, 73%).
（ 1H-NMR，300 MHz，DMSO-d 6）.4.18（s，2H），7.17（q，1H;J 17.5 Hz，J 24.5 Hz），7.43-7.51（m，1H），7.54-7.60（m，2H），
7.67-7.71（m，2H），8.14（dd，1H，J 17.5 Hz，J 21.5 Hz），8.30（dd，1H，J 14.5 Hz，J 21.5 Hz）.
Embodiment XXX III
3-(carbamyl ylmethyl)-the also preparation of [2,3-b] pyridine of 2-phenylpyrrole
Under argon gas atmosphere, with 3-(cyanogen methyl)-2-phenylpyrrole also [2,3-b] pyridine (0.37g, 1.39mmol), powdery KOH(0.82g) and normal-butyl alcohol (5ml) reflux 3 hours.Then reaction mixture is chilled to room temperature,, obtains precipitation with deionization (6.5ml) dilution.The suspension dichloromethane extraction filters.Filter cake is made of pure title compound.
（ 1H-NMR，300 MHz，DMSO-d 6）.3.59（s，2H），6.96-7.03（m，2H），7.33-7.51（m，4H），7.79-7.84（m，2H），8.13（dd，1H，J 17.5 Hz，J 21.5 Hz），8.30（dd，1H，J 14.5 Hz，J 21.5 Hz）.
For clinical use, The compounds of this invention is made medicinal preparations, be used for the administration of oral, enteron aisle, non-enteron aisle or other form.Medicinal preparations contains The compounds of this invention and pharmaceutically acceptable carrier.But carrier solid, semisolid or liquid diluent, or capsule.These medicinal preparationss are another object of the present invention.Usually, the amount of active compound is the 0.1%-95% that accounts for whole weight of formulation.For parenterai administration, the amount of active compound is the 0.2-20% that accounts for weight of formulation, for oral administration, then accounts for the 1-50% of weight of formulation.For the medicinal preparations that contains The compounds of this invention that is used for oral administration with dosage unit form, selected compound can with solid, powder carrier and mix lubricant.Described carrier comprises: for example lactose, sucrose, Sorbitol Powder, mannitol, starch, amylopectin, derivatived cellulose, gelatin or other suitable carrier; Described lubricant comprises: for example Magnesium Stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol wax.Then mixture is made particle or be pressed into tablet.Gelseal can prepare like this: capsule contains one or more The compounds of this invention, vegetables oil, fat or other suitable carrier, hard-gelatin capsules can contain the active ingredient composition granule.Hard-gelatin capsules also can contain and the carrier-bound active compound of solid, powdery, and described carrier comprises: as lactose, sucrose, Sorbitol Powder, mannitol, potato starch, W-Gum, amylopectin, derivatived cellulose or gelatin.
For the dosage device of rectal administration, can make suppository, described suppository contains and sexual fatty substrate blended active substance; Or make the gelatine capsule of rectal administration, described capsule contains active substance and vegetables oil, paraffin oil or is suitable for other carrier of rectum gelatin capsule; Or make ready-made microclyster agent; Or make the microclyster dry preparation, said preparation is before administration, with The suitable solvent preparation again temporarily.
The liquid preparation that is used for oral administration can be made syrup or suspension, for example, contains 0.2-20%(weight) activeconstituents, the solution or the suspension of the mixture that all the other are made up of sugar or sugar alcohol and ethanol, water, glycerine, propylene glycol and polyoxyethylene glycol.In case of necessity, this liquid preparation can contain tinting material, entangle flavor agent, asccharin and carboxymethyl cellulose or other thickening material.The liquid preparation that is used for oral administration also can be made dry powder, allocates with The suitable solvent before use temporarily.
The solution that is used for parenterai administration can be made the solution of the pharmaceutically acceptable solvent of The compounds of this invention, and preferred concentration is 0.1-10%(weight).These solution also can comprise the ampoule and the bottle of stable dosage unit.The solution that is used for parenterai administration also can be made into dry powder doses, prepares with The suitable solvent before use temporarily.
Typical doses every day of active substance can change in very wide scope, and this depends on multiple factor, for example the approach and the disease of each patient's concrete needs, administration.Generally, the scope of oral and non-enteron aisle dosage is generally 5-500mg active substance every day.
Containing The compounds of this invention is illustrated among the following embodiment as the medicinal compositions of activeconstituents:
Preparation A syrup
Be made into following compositions and contain 1%(W/V) syrup of active substance:
The compound 1.0g of embodiment 49
Icing Sugar 30.0g
Asccharin 0.6g
Glycerine 5.0g
Entangle flavor agent 0.05g
96% ethanol 5.0g
Distilled water adds to final volume 100ml
Sugar and asccharin are dissolved in the 60g warm water.After the cooling, this acid salt is dissolved in the ethanolic soln that adds glycerine in the sugar soln then and entangle the flavor agent.Mixture is diluted with water to final volume.
The active substance that provides above can replace with other pharmaceutically acceptable acid-adducting salt.
Preparation B tablet
The tablet that contains the 50mg active compound with the following compositions preparation:
The compound 500g of I embodiment 49
Lactose 700g
Methylcellulose gum 6g
Crosslinked polyvinylpyrrolidone 50g
Magnesium Stearate 15g
Yellow soda ash 6g
Distilled water is an amount of
II hydroxypropylcellulose 36g
Polyoxyethylene glycol 9g
Pigment titanium dioxide 4g
Purified water 313g
I. powdered embodiment 49 compounds are mixed with lactose, granulate with the aqueous solution of methylcellulose gum and yellow soda ash then.Wet material forced sieve, then that particle is dry in baking oven.After the drying, particle is mixed with polyvinylpyrrolidone and Magnesium Stearate.On tabletting machine, with the drift of 7mm diameter the mixture of doing is suppressed (10,000) in flakes, every contains the 50mg active substance.
II. the pure water solution of preparation hydroxypropyl methyl fiber discord polyoxyethylene glycol.After being scattered in titanium dioxide in the tool,, in the Manesty dressing equipment this solution is sprayed on the tablet I at Accela Cota.Obtain the tablet that final weight is 175mg.
Formulation C is used for the solution of intravenously administrable
The parenteral formulation that is used for intravenously administrable with following composition preparation:
Embodiment 49 compound 4g
The poly(oxyethylene glycol) 400 400g that is used to inject
Sodium phosphate dibasic is an amount of
Sterilized water adds to final volume 1,000ml
Embodiment 49 compounds are dissolved in the poly(oxyethylene glycol) 400, add 550ml water then.Add the Sodium phosphate dibasic aqueous solution, PH is transferred to 7.4, add water to the final volume of 1000ml then.Molten, liquid filters with 0.22 μ m strainer, is divided at once then in the aseptic ampoule of 10ml.Ampoule is sealed.
Biological test
A. press people (1976), Acta Physiol.scand. such as Berglindh, 97, the method for 401-414 has been measured the effect of isolated rabbit gastric gland acid excretory vitro inhibition.
The IC of the majority of compounds in the table 1 50Value is in 0.2-100 μ M scope.
B. according to following method, measured restraining effect in the sour excretory body with conscious female rats:
Select Sprague-Dawey family female rats for use.To add stomach (chamber) that the cover fistula is loaded on them the respectively duodenal top that neutralizes, and be used to collect gastric secretions and give test compound.
The operation back allows it that decubation of 14 days is arranged, and begins test then.
Preceding 20 hours of secretion test, animal fasting but can't help water.By gastric intubation tap water (37 ℃) repeatable gastrolavage, wash with 6ml Ringer-Glucose under the same conditions then, at 3h(1.2ml/h., under the same terms) the timed interval in, infusion Peptavlon and carbaminoylcholine (being respectively 20 and 100 nMol/kg.h) gastric acid secretion, during this period of time, collected a gastric secretions in per 30 minutes.Count from beginning to stimulate, after 60 minutes, test compound or vehicle are with the mode administration of intravenous injection or intradermal injection, and consumption is 1ml/kg.To PH=7.0, calculate sour total amount with 0.1 MNaOH solution titration gastric juice sample according to titrating volume and densitometer.Cell mean according to 4-5 rat further calculates.In that time after substances or the vehicle administration, sour total amount is expressed as the mark response, and the sour total amount of regulation administration in the time of preceding 30 minutes is 1.0.Mark RESPONSE CALCULATION according to test compound and vehicle generation goes out to suppress percentage.Diagram interpolation technique according to the dose response logarithmic curve is calculated ED 50Value supposes that perhaps the slope of all dose response curves is identical, estimates ED from single agent test 50Value.The result based on medicine/vehicle administration after the gastric acid secretion thing of bihorium.The ED of embodiment 49 compounds after the intradermal injection administration 50Value is 2 μ mol/kg.
Behind the intravenous administration, the ED of embodiment 63 compounds 50Value is 1.3 μ mol/kg.

Claims (40)

1, formula I compound and pharmacy acceptable salt thereof,
Wherein
Figure 921021704_IMG3
R represents H, low alkyl group, CH 2-O-R 7, halogen, phenyl or by (1-6c) alkyl, (1-6c) alkoxyl group, (1-6C) acyl group, halogen, CF 3, CN, NH 2, NO 2, or (1-6c) phenyl that replaces of alkoxy carbonyl;
R 2Represent H, low alkyl group, CH 2CN,
Figure 921021704_IMG4
, halogen, O-R 8,
Figure 921021704_IMG5
, S-CN, CH 2OH, CH 2C ≡ CH, CF 3, CH 2NC or NH 2
R 3Represent H, low alkyl group, CF 3, O-R 9, NH 2, low-grade alkyl amino, two elementary alkyl amido,
Halogen, CN,
Figure 921021704_IMG6
, S-R 10Or NHCOR 10
R 4And R 5Can be identical or different, represent H, low alkyl group, CN, halogen, O-R 11, nitro, NH 2, low-grade alkyl amino, two elementary alkyl amido, S-R 12, NHCOR 13,
Figure 921021704_IMG7
, CF 3Or R 15-C (O)-;
R 6, R 7, R 8, R 9, R 11And R 13Can be identical or different, represent H or low alkyl group;
R 10Represent low alkyl group or phenyl lower alkyl;
R 12, R 13And R 14Can be identical or different, represent low alkyl group;
R 15Represent H, low alkyl group, OH or lower alkoxy;
Condition is R 1And R 2Not H simultaneously.
2, the compound of claim 1, wherein X is-CO-,
Figure 921021704_IMG8
, or-CH 2-and R 6Be hydrogen or (1-6c) alkyl.
3, the compound of claim 1, wherein R 1Be (1-6c) alkyl, commutable phenyl ,-CH 2OR 7Or halogen, wherein R 7Be hydrogen or (1-6c) alkyl.
4, the compound of claim 1, wherein R 2Be hydrogen, (1-6c) alkyl,
-CH 2C ≡ CH ,-CH 2OH ,-CH 2CN ,-CH 2CONH 2,-CH 2NC ,-NH 2,
Figure 921021704_IMG9
,-SCN, the fontanel element, or-CF 3.
5, the compound of claim 1, wherein R 3Be hydrogen, (1-6c) alkyl ,-OR 9,-NH 2-, (1-6c) alkylamino, (1-6c) dialkyl amido ,-CN ,-SR 10, halogen ,-CF 3Or-NHC OR 10, R wherein 9Be hydrogen or (1-6c) alkyl, and R 10It is (1-6c) alkyl or phenyl-(1-6c)-alkyl.
6, the compound of claim 1, wherein R 4And R 5Can be identical or different, they are selected from: hydrogen, (1-6c) alkyl ,-CN, halogen ,-OR 11,-NO 2,-NH 2, (1-6c) alkylamino, (1-6c) dialkyl amido ,-SR 12,-NHCOR 13,-CF 3Or-COR 15, R wherein 11Be hydrogen or (1-6c) alkyl, R 12Be (1-6c) alkyl, R 13Be hydrogen or (1-6c) alkyl, and R 15Be hydrogen, (1-6c) alkyl, OH, or (1-6c) alkoxyl group.
7, by the compound of claim 1, wherein the definition of X is with claim 2, R 1Definition claim 3, R 2Definition with claim 4, R 3Definition with claim 5, R 4And R 5Definition with claim 6.
8, by the compound of claim 1, wherein X is-CO-,-CH(OH)-,-CH(OCH 3)-,-CH(OC 2H 5)-, or-CH 2-.
9, press the compound of claim 1, wherein R 1Be CH 3, C 2H 5, CH(CH 3) 2, (CH 2) 2CH 3, Cl, Br, or phenyl.
10, press the compound of claim 1, wherein R 2Be H, CH 3, C 2H 5, CH 2CN, CH 2CONH 2, F, Cl, Br ,-SCN, CH 2OH, CH 2C ≡ CH, CF 3, or CH 2NC.
11, press the compound of claim 1, wherein R 3Be
H, CH 3, C 2H 5, CH(CH 3) 2, (CH 2) 2CH 3, CF 3, OH, OCH 3, OC 2H 5, OCH(CH 3) 2, NH 2, NHCH 3, NHC 2H 5, N(CH 3) 2, N(C 2H 5) 2, F, Cl, Br, SCH 3, SC 2H 5, S-CH 2CH 2 , or NHCOCH 3.
12, press the compound of claim 1, wherein R 4And R 5Can be identical or different, they are selected from:
CH, CH 3, C 2H 5, CH(CH 3) 2, F, Cl, Br, OH, OCH 3, OC 2H 5, OCH(CH 3) 2, NO 2, NH 2, NHCH 3, NHC 2H 5, N(CH 3) 2, N(C 2H 5) 2, SCH 3, or CF 3.
13, by the compound of claim 1, wherein the definition of X is with claim 8; R 1Definition with claim 9; R 2Definition with claim 10; R 3Definition with claim 11; R 4And R 5Definition with claim 12.
14, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG11
15, following formula: compound and pharmacy acceptable salt thereof:
16, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG13
17, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG14
18, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG15
19, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG16
20, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG17
21, following formula: compound and the pharmaceutically salt of acceptance:
Figure 921021704_IMG18
22, following formula: compound and pharmacy acceptable salt thereof:
23, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG20
24, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG21
25, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG22
26, following formula: compound and pharmacy acceptable salt thereof:
27, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG24
28, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG25
29, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG26
30, following formula: compound and pharmacy acceptable salt thereof:
Figure 921021704_IMG27
31, contain the medicinal compositions of the compound of arbitrary claim among the claim 1-30 as activeconstituents.
32, the compound of arbitrary claim definition among the claim 1-30 that is used for the treatment of.
33, be used for suppressing the compound of the arbitrary claim definition of claim 1-30 of Mammals and people's gastric acid secretion.
34, the compound that is used for the treatment of arbitrary claim definition among Mammals and people's the claim 1-30 of inflammatory diseases of gastro-intestinal tract.
35, the method that suppresses nurture animal and human gastric acid secretion, the compound administration that is about to arbitrary claim definition among the claim 1-30 is applied to the moving and people of lactation.
36, the method for treatment Mammals and human gastrointestinal tract's inflammatory diseases, this method with the compound administration of arbitrary claim definition among the claim 1-30 in the nurture animal and human.
37, right to be annotated the compound that arbitrary claim defines among the 1-30 and be used to prepare the medicine that suppresses nurture animal and human gastric acid secretion.
38, the compound of arbitrary claim definition among the claim 1-30 is used to prepare the medicine of treatment Mammals and human gastrointestinal tract's inflammatory diseases.
39, the method for the formula I compound of definition in the preparation claim 1, it comprises:
A. with formula II compound and the reaction of formula III compound, formula II and formula III are
Figure 921021704_IMG28
X in the formula, R 1, R 2, R 3, R 4, R 5Definition with to want claim 1, Y be leavings group such as fontanel element, tolysulfonyl oxygen base or mesyloxy;
B. reduce wherein that X is the formula I compound of CO, to prepare wherein R 1, R 2, R 3, R 4And R 5Definition be the formula I compound of CHOH with claim 1 and X;
C. incite somebody to action wherein R 1, R 2, R 3, R 4, R 5With the definition of X with claim 1 and R 2Be-O(1-6c) the formula I compound and the alkylation removal reagent react of alkyl, prepare wherein R 2Be hydroxyl and R 1, R 3, R 4, R 5With the definition of X formula I compound with claim 1;
D. incite somebody to action wherein R 1, R 2, R 3, R 4And R 5Definition with claim 1, X is-formula I compound and the reaction of formula IV compound of CHOH, prepares wherein that X is-CHOR 6And R 1, R 2, R 3, R 4, R 5And R 6Definition with the formula I compound of claim 1, formula IV is
R 6-Z （Ⅳ）
R in the formula 6Definition be the hydroxyl of reactive behavior esterification with claim 1 and Z;
E. incite somebody to action wherein X, R 1, R 2, and R 3Definition with claim 1, R 4Be-O(C 1-C 6) alkyl and R 5Be different from R 4Formula I compound and alkylation removal reagent react, prepare wherein X, R 1, R 2And R 3Definition with claim 1, R 4Be 2 hydroxyls, R 5Be different from R 4The formula I compound;
Then, if necessary, the formula I compound that obtains is transformed into its pharmacy acceptable salt.
40, the method for the claim 39 of the compound that defines among the preparation claim 2-30.
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